Introduction to Pharmacology: core principles, routes of administration, pharmacokinetics & pharmacodynamics

Pharmacology forms the biological bridge connecting basic biomedical sciences to clinical patient management. To practice rational medicine, clinicians must understand both how chemical agents modify body functions and how the human body alters the administered drug over time.

Modern pharmacology divides into multiple clinical and technical specializations that guide research, drug development, formulation, and patient care:

• Pharmacy: The health science discipline dealing with the collection, preparation, preservation, compounding, quality standardization, and proper dispensing of medications.
• Therapeutics (Pharmacotherapeutics): The clinical application of pharmacological knowledge alongside non-pharmacological measures for the prevention, diagnosis, and treatment of disease.
• Chemotherapy: The use of chemical agents designed to selectively eliminate invading microbial pathogens or malignant neoplastic cells while producing minimal toxic damage to normal host tissues (selective toxicity).
• Toxicology: The branch of science concerned with the detection, biological actions, mechanisms, clinical signs, and antidotal management of poisons, toxic environmental substances, and adverse drug overdoses.
• Clinical Pharmacology: The systematic evaluation of pharmacological agents in human beings—including both healthy human volunteers and clinical patient cohorts. It generates objective data on human pharmacokinetics, pharmacodynamics, clinical efficacy, adverse effect profiles, and optimal dosage schedules through controlled comparative clinical trials.

Medications are categorized according to public health necessity, economic development conditions, and legal dispensing regulations.

Therapeutic agents are derived from natural origins, chemical synthesis, or biological recombinant engineering:

The chosen route of drug delivery determines how fast a drug acts, its systemic bioavailability, the intensity of its pharmacological response, and the likelihood of adverse side effects. Selecting the correct route depends on an assessment of several drug-specific and patient-specific factors:

1. Physicochemical Properties of the Drug: Lipid solubility, molecular weight, ionization state, chemical stability at acidic gastric pH, and resistance to enzymatic degradation.
2. Clinical Urgency (Emergency vs. Routine): Rapid-onset routes (such as intravenous injection, sublingual administration, or inhalation) are required for medical emergencies like anaphylaxis, acute pulmonary edema, or status epilepticus; slower oral routes are suited for chronic, routine therapy.
3. Desired Site of Action: Localized application (to minimize systemic drug exposure) versus systemic distribution throughout the body.
4. Clinical Condition of the Patient: Conscious and cooperative versus unconscious, comatose, actively vomiting, or suffering from severe watery diarrhea.
5. Patient Age: Pediatric and geriatric patients may require liquid syrups, rectal suppositories, or injections due to difficulty swallowing solid tablets.
6. Physiological Vulnerability: Susceptibility of the active compound to destruction by gastric hydrochloric acid, intestinal proteases, or extensive first-pass hepatic metabolism.
7. Patient and Clinician Preference: Ease of compliance, cost, pain tolerance, and the feasibility of self-administration outside of hospital settings.

The local route involves administering a drug directly to the anatomical site where its pharmacological action is required. By concentrating the agent locally, systemic absorption is reduced, which helps minimize systemic adverse effects.

The systemic route requires the administered drug to enter the bloodstream so it can distribute throughout the vascular and extravascular tissues to reach its site of action. Systemic delivery is divided into enteral routes (using the alimentary canal) and parenteral routes (bypassing the digestive tract).

1. Oral Route (Per Os - P.O.)

The oral route is the most common, convenient, and widely accepted method of systemic drug delivery. Common pharmaceutical formulations include compressed tablets, gelatin capsules, oral suspensions, syrups, elixirs, and mixtures (e.g., paracetamol tablets for pyrexia, or omeprazole capsules for peptic ulcer disease).

2. Sublingual and Buccal Routes

In the sublingual route, a tablet or spray is placed directly beneath the tongue. In the buccal route, the medication is placed between the cheek and upper gingiva. The drug dissolves and diffuses across the non-keratinized oral mucous membrane directly into the rich local capillary bed.

• Clinical Examples: Sublingual glyceryl trinitrate (nitroglycerin) tablets or spray for relieving acute angina pectoris; sublingual buprenorphine for managing severe pain in acute myocardial infarction or opioid dependence.
• Advantages: Fast onset of action; can be terminated quickly by spitting out the remaining tablet if excessive hypotension or adverse effects develop; avoids destruction by gastric acid and digestive enzymes; allows easy self-administration.
• Disadvantages: Restricted to lipid-soluble, highly potent drugs required in small milligram quantities; unsuitable for foul-tasting, bitter, or locally irritant chemicals.

3. Rectal Route for Systemic Delivery

The rectum provides an alternative enteral route for patients who cannot take oral medications due to unconsciousness, intractable vomiting, or status epilepticus. Medications are formulated as solid suppositories that melt at body temperature, or as liquid enemas:

• Systemic Suppository Example: Rectal indomethacin (NSAID) for managing systemic joint inflammation and pain in rheumatoid arthritis; paracetamol suppositories for pediatric fever.
• Systemic Enema Example: Rectal administration of diazepam solution for emergency termination of prolonged pediatric status epilepticus when intravenous access cannot be established.
• Partial First-Pass Sparing: The venous drainage of the rectum is anatomically divided. The inferior and middle rectal veins drain directly into the internal iliac veins and inferior vena cava, bypassing the liver (~50%). However, the superior rectal vein drains into the inferior mesenteric vein and the hepatic portal system. As a result, rectal first-pass avoidance is only partial (~50%) and can vary based on suppository placement.

The term parenteral (from Greek para, beside; enteron, intestine) encompasses all routes that deliver medications directly into body fluids, tissues, or vascular channels outside the alimentary canal. Parenteral administration requires sterile equipment, precise anatomical knowledge, and controlled injection angles.

Anatomical Sites for Intramuscular Injection

To avoid neurovascular injury, specific anatomical landmarks must be identified prior to inserting an intramuscular needle:

The intravenous (I.V.) route involves introducing a drug solution directly into the lumen of a superficial or deep vein, placing the chemical directly into systemic venous return without an absorption barrier.

Methods of Intravenous Delivery

1. Intravenous Bolus: A single, relatively concentrated dose of a drug injected over a short duration (seconds to a few minutes). Used to achieve rapid therapeutic plasma concentrations, such as intravenous ranitidine or proton-pump inhibitors for acute bleeding peptic ulcers, or IV adenosine for supraventricular tachycardia.
2. Slow Intravenous Injection: Administered carefully over several minutes (e.g., 5 to 10 minutes) to avoid sudden cardiovascular depression, such as slow intravenous morphine for severe ischemic pain in acute myocardial infarction, or slow IV aminophylline for refractory bronchospasm.
3. Continuous Intravenous Infusion: Controlled administration of a drug diluted in a carrier solution (such as normal saline or 5% dextrose) over hours or days using an infusion pump or gravity drip:
   • To titrate and maintain a steady-state plasma concentration, such as continuous dopamine or noradrenaline infusion in cardiogenic or septic shock.
   • To deliver hypertonic solutions for intracranial hypertension, such as 20% mannitol infusion in acute cerebral edema.
   • To replace fluid and electrolytes in severe dehydration, hypovolemic shock, or diabetic ketoacidosis.

Specialized parenteral routes allow targeted drug delivery to internal compartments or provide controlled, long-term release through the skin and other tissues.

1. Inhalation for Systemic Effects

Volatile liquids and gases pass across the alveolar capillary membrane into pulmonary venous blood, reaching the arterial circulation rapidly without first-pass hepatic clearance:

• Clinical Applications: General anesthesia using volatile liquids (e.g., halothane, isoflurane, sevoflurane) and medical gases (e.g., nitrous oxide).
• Advantages: Very rapid onset and recovery; depth of anesthesia can be adjusted breath-by-breath by altering the vaporizer concentration.
• Disadvantages: Certain volatile vapors can cause tracheobronchial irritation, leading to increased respiratory secretions, cough, and reflex bronchospasm.

2. Intrathecal Route

Direct injection of a sterile drug solution through a spinal needle into the subarachnoid space (lumbar cistern below the level of the conus medullaris). This bypasses the blood–brain and blood–cerebrospinal fluid barriers:

• Clinical Examples: Spinal anesthesia using hyperbaric lignocaine or bupivacaine for pelvic and lower-extremity surgery; intrathecal administration of amphotericin B for life-threatening fungal meningitis (e.g., cryptococcal meningitis).

3. Transdermal Drug Delivery Systems (TDDS)

Application of an adhesive patch or ointment to intact skin that releases drug continuously at a controlled rate across the stratum corneum into the dermal microcirculation for systemic distribution:

• Clinical Examples: Transdermal hyoscine (scopolamine) patch placed over the mastoid process for motion sickness and sialorrhea; transdermal glyceryl trinitrate (nitroglycerin) patch or ointment for prophylaxis against angina pectoris; and transdermal estrogen (estradiol) patches for hormone replacement therapy (HRT).
• Key Advantages: Provides stable, continuous plasma drug concentrations without daily peaks and troughs; avoids first-pass hepatic metabolism; improves patient compliance by reducing dosing frequency.

4. Advanced & Novel Drug Delivery Systems

• Ocusert: A flexible elliptical wafer placed into the lower conjunctival cul-de-sac. For example, a pilocarpine ocusert releases the miotic agent at a zero-order rate over seven continuous days for open-angle glaucoma, avoiding the need for multiple daily eye drops.
• Intraoral Lignocaine Patch: A mucoadhesive patch applied directly to the buccal mucosa to provide localized surface anesthesia prior to dental procedures.
• Jet Injection (Needle-Free): High-pressure micro-jets of liquid that penetrate the epidermis and submucosa without a hypodermic needle to deliver local anesthetics or vaccines.
• Liposomes: Microscopic vesicles composed of concentric phospholipid bilayers enclosing an aqueous core. Water-soluble drugs are encapsulated within the core and lipid-soluble drugs within the lipid layers (e.g., liposomal amphotericin B). Liposomal packaging reduces systemic nephrotoxicity while directing the drug toward fungal cell membranes.
• Monoclonal Antibodies (Targeted Delivery): Laboratory-engineered immunoglobulins directed against specific molecular targets, such as cell-surface receptors on malignant cancer cells (e.g., trastuzumab targeting HER2 in breast cancer, or antibody-drug conjugates delivering cytotoxic payloads directly to tumors).

Most therapeutic drugs produce their effects by interacting with macromolecular proteins called receptors. A drug's ability to bind to and activate a receptor depends on two key properties:

Antagonism occurs when one chemical agent reduces, attenuates, or abolishes the pharmacological effect of another drug or endogenous ligand. Drug antagonism is divided into four major mechanisms:

1. Physical Antagonism

Neutralization of a drug based on its physical properties, without a chemical reaction or receptor interaction.

For example, oral administration of activated charcoal adsorbs alkaloids and organic toxins onto its porous surface within the gastrointestinal lumen, preventing systemic absorption in acute poisoning.

2. Chemical Antagonism

Two chemicals react directly with one another in solution to form an inactive, non-toxic compound:

• Potassium Permanganate (KMnO₄): A strong oxidizing agent added to gastric lavage solutions to oxidize and inactivate alkaloids in gastric poisonings.
• Tannins: Precipitate ingested alkaloids into insoluble alkaloidal tannates in the stomach.
• Chelating Agents: Organic molecules that bind heavy metal ions to form stable, non-toxic, water-soluble ring complexes that are excreted in urine (e.g., dimercaprol / BAL for arsenic, gold, and mercury poisoning; calcium disodium edetate / EDTA for lead poisoning).
• Nitrites in Cyanide Poisoning: Sodium nitrite oxidizes ferrous hemoglobin (Fe²⁺) to methemoglobin (Fe³⁺), which binds free cyanide ions with high affinity, pulling them away from cytochrome c oxidase.

3. Physiological (Functional) Antagonism

Two drugs act on completely different receptor types or through separate signaling pathways, producing opposing physiological actions on the same organ system:

• Histamine vs. Adrenaline: Histamine acts on H₁ receptors to cause bronchoconstriction and systemic vasodilation (causing severe hypotension in anaphylactic shock). Adrenaline (epinephrine) acts on β₂-adrenoceptors to cause bronchodilation and α₁-adrenoceptors to cause peripheral vasoconstriction, reversing the respiratory and cardiovascular effects of histamine.

4. Receptor Antagonism

An antagonist binds directly to a receptor, preventing its activation by endogenous ligands or exogenous agonists:

Repeated or continuous administration of certain pharmacological agents leads to progressive changes in tissue responsiveness and biological dependence.

Drug Tolerance

Tolerance is defined as a progressive decrease in pharmacological response following repeated administration of a drug. As a result, higher doses are required to achieve the original therapeutic effect.

Tachyphylaxis (Acute Tolerance)

Tachyphylaxis is the rapid, acute development of tolerance after only a few initial doses of a drug, occurring within minutes to hours. Unlike classic tolerance, simply increasing the drug dose cannot restore the initial biological response because the underlying neurochemical stores are exhausted:

• Mechanism: Indirectly acting sympathomimetic amines (e.g., ephedrine, tyramine, amphetamine) act by displacing stored noradrenaline from presynaptic vesicles into the synaptic cleft. Repeated doses deplete these vesicular stores, leaving no transmitter available to produce a response on subsequent administration.

Drug Dependence

The World Health Organization (WHO) defines drug dependence as: "A state—psychic and sometimes also physical—resulting from the interaction between a living organism and a drug, characterized by behavioral and other responses that always includes a compulsion to take the drug on a continuous or periodic basis in order to experience its psychic effects, and sometimes to avoid the discomfort of its absence."

• Psychological (Psychic) Dependence: An intense emotional or mental craving to continue taking a drug to produce pleasure or relieve underlying anxiety, without clear physiological withdrawal signs upon cessation.
• Physical Dependence: An altered physiological state where repeated drug exposure causes homeostatic adaptations in the central nervous system (such as receptor down-regulation or enzymatic adjustments), making the continuous presence of the drug necessary to maintain normal body function.
• Withdrawal (Abstinence) Syndrome: Abrupt cessation of a drug in a physically dependent individual causes an acute rebound homeostatic imbalance, producing clinical signs and symptoms that are directly opposite to the acute pharmacological actions of the drug (e.g., opioid withdrawal causes severe diarrhea, pupillary dilation, rhinorrhea, muscle spasms, and severe anxiety). Common agents that cause physical dependence include opioids, alcohol, barbiturates, benzodiazepines, and amphetamines.

Adverse drug reactions include abnormal genetic responses as well as immune-mediated hypersensitivity reactions.

1. Drug Idiosyncrasy (Pharmacogenetic Reactions)

Idiosyncrasy is a genetically determined, qualitatively abnormal or bizarre response to a drug that occurs on initial exposure, unrelated to known pharmacological actions or immune-mediated allergy:

2. Drug Allergies (Immune-Mediated Hypersensitivity)

A drug allergy is an adverse response to an exogenous chemical agent mediated by the host immune system. Prior exposure to the drug (or a cross-reactive structure) is required to prime or sensitize the immune system.

Drug-induced hypersensitivity reactions follow the classic Gell and Coombs classification:

The term pharmacokinetics is derived from the Greek pharmakon (drug) and kinesis (motion). It describes what the body does to the drug over time.

Absorption is the process by which a drug moves from its site of administration into the systemic circulation. To be absorbed, drug molecules must cross biological lipid membranes:

Physiological Mechanisms of Drug Permeation

1. Passive Diffusion: The most common mechanism of drug permeation. It is a non-energy-dependent, bidirectional process driven purely by the concentration gradient:
   • Substances move from an area of higher concentration to one of lower concentration until dynamic equilibrium is reached.
   • The rate of transfer is directly proportional to the concentration gradient, according to Fick's law of diffusion.
   • It favors small, unionized, highly lipid-soluble molecules that can dissolve into and cross the hydrophobic core of the phospholipid bilayer.
2. Filtration (Aqueous Diffusion): The passage of small, water-soluble molecules through aqueous protein channels or intercellular junctional pores:
   • Depends on the molecular weight and size of the drug relative to pore diameter.
   • Most capillaries (except the blood–brain barrier) have large intercellular fenestrations (40 to 45 Å), allowing molecules smaller than albumin to filter through into interstitial fluid.
3. Specialized Carrier-Mediated Transport:
   • Active Transport: Movement of a drug molecule against its concentration gradient (from low to high concentration). This process is saturable, requires metabolic energy (ATP consumption), can be competitively inhibited, and uses specialized membrane carrier proteins. Examples include uptake of sympathomimetic amines into adrenergic nerve terminals, transport of choline into cholinergic neurons, and intestinal absorption of levodopa via large neutral amino acid transporters.
   • Facilitated Diffusion: A carrier-mediated process that operates down a concentration gradient (from high to low concentration). It requires a membrane transporter but requires no metabolic energy. It is subject to saturation kinetics and competitive inhibition. An example is the transport of glucose across skeletal muscle and adipose cell membranes via the insulin-sensitive GLUT4 transporter.

Drug distribution is the reversible transfer of a drug between body fluid compartments (from the vascular compartment into the interstitial and intracellular spaces).

Apparent Volume of Distribution (V_d)

The Apparent Volume of Distribution (V_d) is a hypothetical volume of body fluid into which an administered dose would need to distribute to achieve a concentration equal to that found in blood plasma, assuming the body acts as a single homogeneous compartment:

Plasma Protein Binding Dynamics

Upon entering the circulation, many drugs bind reversibly to circulating plasma proteins:

• Plasma Albumin: The primary carrier protein for acidic drugs (such as aspirin, sulphonamides, penicillin, phenytoin, and warfarin).
• α₁-Acid Glycoprotein: The primary carrier protein for basic drugs (such as lignocaine, bupivacaine, propranolol, and diazepam).

Clinical Consequences of Plasma Protein Binding

1. Promotes Drug Absorption: Plasma protein binding keeps free drug concentrations in capillary blood low, preserving the concentration gradient that drives absorption across mucosal barriers.
2. Influences Volume of Distribution: Extensive binding to plasma proteins keeps the drug within the bloodstream, producing a small apparent volume of distribution (V_d).
3. Delays Metabolism & Glomerular Filtration: Large drug-protein complexes cannot pass through glomerular capillary pores or enter hepatocytes, slowing clearance.
4. Extends Duration of Action: Bound drug dissociates over time to replenish free drug levels as they decline. For example, sulphadiazine is less protein-bound and has a short half-life of 6 hours, whereas sulphadoxine is highly protein-bound and has a half-life of roughly one week.
5. Limits Hemodialysis: In acute poisoning, drugs that are heavily bound to plasma proteins (or have large V_d values) cannot be efficiently cleared from the blood by hemodialysis.
6. Hypoalbuminemia Toxicity: In conditions that lower plasma albumin levels (e.g., severe malnutrition, nephrotic syndrome, chronic liver cirrhosis), the free fraction of acidic drugs rises, increasing the risk of toxicity at normal therapeutic doses.
7. Competitive Displacement Interactions: When two highly protein-bound drugs compete for the same binding sites on albumin, the drug with higher affinity displaces the one with lower affinity. This causes an acute rise in the displaced drug's free concentration, which can produce toxicity (e.g., sulphonamides displacing warfarin can cause severe hemorrhage; sulphonamides displacing bilirubin in neonates can cause kernicterus).

Metabolism (Biotransformation) is the enzymatic chemical alteration of a drug within a living organism. Its primary purpose is to convert lipophilic, unionized molecules into water-soluble, ionized compounds that can be readily excreted in urine or bile. Highly polar, water-soluble drugs do not undergo extensive metabolism and are excreted unchanged by the kidneys.

The liver is the primary metabolic organ in the body. Other tissues that contribute to drug biotransformation include the gastrointestinal tract mucosa, kidneys, lungs, circulating blood plasma, skin, and placenta.

Outcomes of Metabolic Biotransformation

• Inactivation of an Active Drug (Most Common): Converts an active parent compound into an inactive, polar metabolite:
  • Phenobarbitone → Hydroxyphenobarbitone
  • Phenytoin → para-Hydroxyphenytoin
• Conversion of an Active Drug into an Active Metabolite: The metabolite retains pharmacological activity, extending the clinical duration of action:
  • Codeine → Morphine (potent analgesia via CYP2D6)
  • Diazepam → Desmethyldiazepam → Oxazepam
• Activation of an Inactive Prodrug: The parent drug is pharmacologically inactive and requires enzymatic cleavage or conversion in the body to generate the active therapeutic compound:
  • Levodopa → Dopamine (converted by aromatic L-amino acid decarboxylase in the brain)
  • Prednisone → Prednisolone (converted by 11β-hydroxysteroid dehydrogenase in the liver)

Phase I and Phase II Reactions

Biotransformation reactions are broadly grouped into two sequential phases:

Enzyme Induction and Inhibition

Drug excretion is the irreversible physical removal of an active drug and its metabolites from the body. The primary excretory organ is the kidney, supported by secondary pathways including the biliary tract, lungs, intestines, sweat, saliva, tears, and breast milk.

Renal Excretion Mechanisms

The kidney clears drugs through three distinct physiological processes:

1. Glomerular Filtration: Hydrostatic pressure in glomerular capillaries forces fluid and dissolved solutes through endothelial fenestrations and podocyte slit diaphragms into Bowman's space. All free, unbound drugs with molecular weights below albumin filter into the primary filtrate; protein-bound fractions remain in the blood. Glomerular filtration facilitates drug excretion.
2. Active Tubular Secretion: Active, energy-dependent carrier systems located in the proximal convoluted tubule pump organic ions from peritubular capillaries into the tubular lumen:
   • Organic Anion Transporters (OAT): Secrete acidic drugs like penicillins, cephalosporins, thiazide diuretics, and methotrexate.
   • Organic Cation Transporters (OCT): Secrete basic drugs like morphine, procainamide, and trimethoprim.
   • Active tubular secretion is independent of plasma protein binding and facilitates drug excretion.
3. Passive Tubular Reabsorption: As water is reabsorbed along the nephron, the concentration of filtered drug in the tubular lumen rises:
   • Lipid-soluble, unionized drug molecules passively diffuse out of the lumen across tubular epithelial cells and return to peritubular capillary blood.
   • Passive tubular reabsorption decreases drug excretion.
   • Ionized, polar drug molecules are trapped in the tubular lumen and eliminated in urine (ion trapping). Alkalinizing the urine (e.g., with sodium bicarbonate) ionizes weak acids like aspirin and phenobarbitone, accelerating their elimination in overdose.

Extra-Renal Elimination Routes

• 1. Pulmonary Route (Lungs): Volatile substances and gases are eliminated across the alveolar-capillary membrane during expiration. Examples include ethanol (providing the physiological basis for breathalyzer testing) and volatile general anesthetics like halothane, isoflurane, and ether.
• 2. Fecal Route: Unabsorbed oral medications remain within the intestinal lumen and are excreted in feces (e.g., non-absorbable purgatives like senna and cascara).
• 3. Biliary Excretion & Enterohepatic Circulation:
• 4. Cutaneous Route (Skin): Heavy metals like arsenic and mercury deposit in skin keratin, hair, and nails, providing a biological record used in forensic toxicology.
• 5. Salivary Excretion: Certain drugs diffuse into saliva, including potassium iodide, phenytoin, metronidazole, and lithium. Measuring salivary lithium levels provides a non-invasive way to monitor therapeutic drug concentrations without repeated venipunctures.
• 6. Mammary Excretion (Breast Milk): Breast milk has a slightly more acidic pH (pH ∼ 7.0–7.2) than maternal blood plasma (pH ∼ 7.4). Because of this pH difference, weakly basic drugs become trapped in their ionized form within breast milk:
  • Basic drugs like morphine, diazepam, tetracycline, and chloramphenicol cross into breast milk, exposing the nursing infant to the drug and its potential adverse effects.