Principles of General Pharmacology

This chapter introduces the fundamental principles of modern pharmacology, the science of drug action. For a BAMS student, this knowledge is crucial for understanding the scientific basis of drug therapy, enabling integrated practice, and building a bridge between the concepts of Dravyaguna (like Virya, Vipaka) and modern concepts of drug mechanisms (like receptors, ADME).

Introduction to Pharmacology

Pharmacology comes from the Greek words: Pharmakon (meaning "drug") and Logos (meaning "study"). It is the science that deals with the mechanism of action, uses, adverse effects, and fate of drugs in the body.

Drug: According to the WHO, a drug is "any substance or product that is used or intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient."

Pharmacology is divided into two main branches:

1. Pharmacokinetics (PK)
2. Pharmacodynamics (PD)

Pharmacokinetics (PK): "What the Body does to the Drug"

Pharmacokinetics describes the journey of a drug through the body. It involves the study of the time course of drug ADME: Absorption, Distribution, Metabolism, and Excretion.

1. Absorption (A)

This is the process by which a drug moves from its site of administration (e.g., the gut) into the systemic circulation (the bloodstream).

Mechanisms of Drug Absorption:

• Passive Diffusion: The most common mechanism. The drug moves across a cell membrane from an area of high concentration to low concentration. It does not require energy. This process favors drugs that are lipid-soluble (lipophilic).
• Facilitated Diffusion: The drug moves across the membrane with the help of a carrier protein, but still down its concentration gradient. It does not require energy.
• Active Transport: The drug is moved across the membrane by a carrier protein against its concentration gradient. This process is selective and requires energy (ATP).

Factors Affecting Absorption:

• Route of Administration: IV (Intravenous) route gives 100% absorption instantly. Oral route is slower and absorption may be incomplete.
* Drug Properties: Lipid solubility, molecular size, and pKa (ionization) of the drug.
• First-Pass Metabolism: When a drug is taken orally, it is absorbed from the gut and travels via the portal vein directly to the liver. A significant portion of the drug may be metabolized (broken down) by the liver *before* it even reaches the systemic circulation. This reduces the amount of active drug available to the body.

2. Distribution (D)

This is the process by which the drug, once in the bloodstream, is reversibly transferred to various tissues and fluids of the body.

Factors Affecting Distribution:

• Blood Flow: Organs with high blood supply (e.g., brain, liver, kidneys) receive the drug first.
• Plasma Protein Binding: Many drugs bind to proteins in the plasma (like Albumin). A drug that is bound to a protein is inactive and cannot leave the bloodstream. Only the "free" (unbound) drug is active and can be distributed to tissues.
• Tissue Barriers: Special barriers like the Blood-Brain Barrier (BBB) restrict the entry of many drugs into the brain, protecting it.
• Volume of Distribution (Vd): A theoretical volume that describes how extensively a drug is distributed in the tissues vs. remaining in the plasma. A high Vd means the drug is concentrated in the tissues; a low Vd means it is mostly in the blood.

3. Metabolism (M) or Biotransformation

This is the chemical alteration or breakdown of the drug by the body, primarily in the Liver. The goal is to convert the drug (which is often lipid-soluble) into a water-soluble (polar) compound so it can be easily excreted by the kidneys.

Metabolic Reactions:

• Phase I Reactions (Functionalization): These reactions (like Oxidation, Reduction, Hydrolysis) introduce or unmask a functional group. They are primarily carried out by the Cytochrome P450 (CYP450) family of enzymes in the liver.
• Phase II Reactions (Conjugation): These reactions join the drug (or its Phase I metabolite) with an endogenous substance (like glucuronic acid). This makes the drug highly water-soluble and ready for excretion.

4. Excretion (E)

This is the process of removal of the drug and its metabolites from the body.

Major Routes of Excretion:

• Renal (Kidney): The most important route. Drugs are removed via urine. This involves three processes:
  1. Glomerular Filtration: Free drug is filtered from the blood.
  2. Tubular Secretion: Active transport of drugs from blood into the urine.
  3. Tubular Reabsorption: Lipid-soluble drugs can be passively reabsorbed from the urine back into the blood, which prolongs their action.
• Hepatic (Bile): Drugs are excreted by the liver into the bile, which then enters the intestine and is eliminated in the feces.
• Other Routes: Lungs (for anesthetic gases), sweat, saliva, and breast milk.

Pharmacodynamics (PD): "What the Drug does to the Body"

Pharmacodynamics is the study of the biochemical and physiological effects of drugs and their **Mechanism of Action (MOA)**. It explains *how* a drug produces its effect.

Mechanism of Action (MOA)

Most drugs produce their effects by interacting with specific target molecules in the body, most commonly Receptors.

1. Receptors

Receptors are protein molecules (usually on the cell surface or inside the cell) that act like a "lock." A drug (or a natural body chemical) acts as a "key" (or Ligand) that binds to this lock, causing a change in the cell's function.

• Agonist: A drug that binds to and activates a receptor, producing a biological response. (A key that fits and opens the lock).
• Antagonist: A drug that binds to a receptor but does not activate it. It "blocks" the receptor, preventing the body's natural agonist from binding. (A key that fits in the lock but breaks off, jamming it).
• Partial Agonist: A drug that binds and activates a receptor, but only produces a weak or partial response, even at high doses.

2. Other Drug Targets

• Enzymes: Drugs can inhibit or activate enzymes (e.g., Aspirin inhibits the COX enzyme).
• Ion Channels: Drugs can block or open ion channels in cell membranes (e.g., Calcium Channel Blockers).
• Non-Specific Action: Some drugs work through simple physical or chemical properties (e.g., Antacids neutralize stomach acid; Laxatives add bulk).

Key Pharmacological Concepts

1. Dose-Response (D-R) Curve

This is a graph that plots the dose of a drug against the intensity of the response it produces. From this curve, we can determine two key properties:

• Potency: The *amount* of drug needed to produce a specific effect. A drug that produces an effect at a lower dose is more potent.
• Efficacy: The *maximum* effect a drug is capable of producing, regardless of the dose.

2. Therapeutic Index (TI)

The Therapeutic Index is a measure of a drug's **safety**. It is the ratio between the dose that causes a toxic effect and the dose that produces a therapeutic effect.

$$TI = \frac{LD_{50}}{ED_{50}}$$

• $ED_{50}$ (Median Effective Dose): The dose that produces a therapeutic effect in 50% of the population.
• $LD_{50}$ (Median Lethal Dose): The dose that is lethal to 50% of the population.

A Wide Therapeutic Index means a drug is relatively safe. A Narrow Therapeutic Index means a drug is risky, and the dose must be carefully monitored (e.g., Digoxin).

3. Half-Life ($t_{\frac{1}{2}}$)

The half-life of a drug is the time it takes for the concentration of the drug in the plasma to be reduced by half (50%). Half-life is important because it determines the dosing frequency (i.e., how many times a day you need to take the drug to maintain its effect).

4. Drug Incompatibility & Interactions

When two or more drugs are taken together, they can interact, leading to altered effects.

• Pharmacokinetic Interaction: One drug affects the ADME of another (e.g., one drug blocks the metabolism of another, leading to toxicity).
• Pharmacodynamic Interaction:
  • Synergism (Additive): The combined effect is equal to the sum of individual effects ($1 + 1 = 2$).
  • Potentiation: One drug enhances the effect of another ($1 + 0 = 2$).
  • Antagonism: One drug reduces or blocks the effect of another ($1 + 1 = 0$).

Exam-Oriented Questions

Long Answer Questions (10 Marks)

1. Define Pharmacology. Explain its two main branches: Pharmacokinetics and Pharmacodynamics, in detail.
2. What is Pharmacokinetics? Explain the four processes of ADME (Absorption, Distribution, Metabolism, Excretion) with factors affecting them.
3. What is Pharmacodynamics? Explain the Mechanism of Action of drugs with reference to Receptors, Agonists, and Antagonists.
4. Write a detailed note on the key principles of modern pharmacology, including Dose-Response Curve, Therapeutic Index, and Half-Life.
5. Write a comparative note on Modern Pharmacology (ADME, Receptors) and Ayurvedic Pharmacology (Vipaka, Virya, Prabhava).

Short Answer Questions (5 Marks)

• Differentiate between Pharmacokinetics and Pharmacodynamics.
• What is 'Absorption'? Explain different mechanisms of drug absorption (Passive, Active).
• What is 'First-Pass Metabolism' and how does it affect 'Bioavailability'?
• Explain Phase I and Phase II metabolism. What is the role of CYP450 enzymes?
• Define Receptors. Differentiate between an Agonist and an Antagonist.
• What is the 'Therapeutic Index'? Why is a drug with a narrow TI considered unsafe?
• Explain the Ayurvedic concepts of 'Virya' and 'Prabhava' as the basis for Pharmacodynamics.
• How does the Ayurvedic concept of 'Anupana' and 'Viruddha Ahara' relate to modern principles of absorption and drug interactions?

Very Short Answer Questions (2 Marks)

• Define Pharmacology.
• Define Pharmacokinetics.
• Define Pharmacodynamics.
• What does ADME stand for?
• Define 'Bioavailability'.
• Define 'Half-Life' ($t_{\frac{1}{2}}$).
• What is 'First-Pass Metabolism'?
• Differentiate between Potency and Efficacy.
• What is the modern correlation for 'Vipaka'? (Metabolism)
• What is the modern correlation for 'Prabhava'? (Specific Receptor Action)
• What is 'Viruddha Ahara'? (Incompatibility / Drug-Food Interaction)