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📚 M. PHARM - SEMESTER I

ADVANCED PHARMACOLOGY-I (MPL 102T)

UNIT 1: GENERAL PHARMACOLOGY

Simple Language | Standard Academic Format

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PART A: PHARMACOKINETICS

Definition: Pharmacokinetics (PK) = "What the body does to the drug" It studies the ADME processes: Absorption, Distribution, Metabolism (Biotransformation), Excretion.

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1. ABSORPTION

Mechanisms of Membrane Transport:

Henderson-Hasselbalch Equation (Ion Trapping):

• Most drugs are weak acids or weak bases
• pKa = pH at which 50% drug is ionized
• Weak acid drugs: better absorbed in stomach (pH 1-2, mostly non-ionized)
• Weak base drugs: better absorbed in intestine (pH 5-8, mostly non-ionized)
• Despite the above, intestine absorbs both better due to its massive surface area (~200 m²)
• Ion trapping: Acidic drug accumulates on the basic side of a membrane; basic drug on the acidic side

Factors Affecting Absorption:

1. Physicochemical - lipid solubility, pKa, molecular size, ionization state
2. Physiological - GI pH, motility, surface area, blood flow, P-glycoprotein efflux
3. Dosage form - dissolution rate (solution > suspension > capsule > tablet > coated tablet)
4. Food - delays or reduces absorption of many drugs; but some need food (e.g., griseofulvin)

Bioavailability (F):

• Definition: Fraction of administered dose that reaches the systemic circulation unchanged
• Formula: F = Quantity reaching systemic circulation / Quantity administered (value: 0 to 1 or 0 to 100%)
• IV route = 100% bioavailability (gold standard)
• First-pass effect: Oral drug is absorbed from GI tract → enters portal vein → liver metabolizes it before it enters systemic circulation → reduces bioavailability (e.g., propranolol, lidocaine, morphine)
• AUC (Area Under Curve): Area under plasma concentration-time curve; reflects total drug exposure; used to calculate bioavailability

Routes of Administration - Comparison:

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2. DISTRIBUTION

Key Determinant - Blood Flow:

• Well-perfused organs get drug first: liver, kidney, brain, heart
• Poorly perfused get drug later: muscle, fat, skin

Volume of Distribution (Vd):

• Definition: Hypothetical volume of fluid in which the drug would need to be uniformly distributed to produce the observed plasma concentration
• Formula: Vd = Dose / Plasma concentration
• High Vd (>1 L/kg) = drug extensively distributed into tissues (e.g., chloroquine)
• Low Vd (~0.07 L/kg) = drug confined to plasma (e.g., heparin, warfarin)

Plasma Protein Binding:

• Many drugs bind to plasma proteins (mainly albumin for acidic drugs; α1-acid glycoprotein for basic drugs)
• Only free (unbound) drug is pharmacologically active, filtered by kidney, and metabolized
• Binding is reversible; acts as a drug reservoir
• Clinical significance:
  • Drug displacement interactions (e.g., warfarin displaced by aspirin → increased bleeding risk)
  • Hypoalbuminemia (liver disease, malnutrition) → more free drug → toxicity
  • Only free drug crosses blood-brain barrier (BBB) and placenta

Special Barriers:

1. Blood-Brain Barrier (BBB): Tight junctions + astrocytes; only lipophilic, non-ionized, unbound drugs cross; protects CNS
2. Placental barrier: Less restrictive; lipophilic drugs cross; risk of fetal drug exposure
3. Blood-Testis Barrier: Similar to BBB

Tissue Binding:

• Drugs may bind to tissues (e.g., tetracycline in bone/teeth, chloroquine in retina)
• Creates tissue reservoirs → prolonged action or toxicity

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3. METABOLISM (BIOTRANSFORMATION)

Types of Reactions:

• Add or unmask a functional group (-OH, -NH2, -SH, -COOH)
• Make drug more polar
• Usually produce an active or toxic metabolite
• Reactions: Oxidation (most common), Reduction, Hydrolysis
• Main enzyme: Cytochrome P450 (CYP450) - located in liver microsomes (ER)
  • Major isoforms: CYP3A4 (most important, ~50% of drugs), CYP2D6, CYP2C9, CYP2C19, CYP1A2

• Add a large polar molecule to the drug or Phase I metabolite
• Almost always inactivate the drug
• Produce water-soluble conjugates → excreted in urine or bile
• Reactions: Glucuronidation (most common), Sulfation, Acetylation, Methylation, Glutathione conjugation, Glycine conjugation

Enzyme Induction vs. Inhibition:

First-Pass Metabolism:

• Oral drug absorbed from intestine → portal vein → liver → significant metabolism before systemic circulation
• High first-pass drugs: morphine, propranolol, lidocaine, GTN, aspirin (partial)
• Ways to bypass: sublingual, IV, IM, SC, transdermal, rectal (partial)

Prodrugs:

• Pharmacologically inactive drug that is converted to active form in the body
• Examples: enalapril → enalaprilat; codeine → morphine; levodopa → dopamine

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4. EXCRETION (ELIMINATION)

Renal Excretion (Most Important):

1. Glomerular Filtration: Only free (unbound) drug is filtered (GFR ~125 mL/min)
2. Active Tubular Secretion: Carrier-mediated; can secrete protein-bound drug too; saturable
   • Acidic drug carriers: furosemide, penicillin, indomethacin
   • Basic drug carriers: dopamine, histamine, amiloride
3. Passive Tubular Reabsorption: Lipophilic/non-ionized drugs are reabsorbed back; ionic form remains in tubule and is excreted
   • pH manipulation for poisoning:
     • Alkalize urine (sodium bicarbonate) → ionizes weak acids → faster excretion (e.g., aspirin, phenobarbitone overdose)
     • Acidify urine (ammonium chloride) → ionizes weak bases → faster excretion (e.g., amphetamine)

Biliary/Fecal Excretion:

• Liver excretes drugs into bile → intestine → feces
• Enterohepatic circulation: Drug excreted in bile is re-absorbed from intestine → prolonged effect (e.g., morphine, oral contraceptives, chloramphenicol)

Other Routes:

• Lungs: Volatile/gaseous drugs (anesthetic gases, alcohol)
• Breast milk: Important for nursing infants (basic drugs concentrate in milk as milk is slightly acidic)
• Sweat, saliva, tears: Minor

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5. PHARMACOKINETIC PARAMETERS

Half-Life (t₁/₂):

• Definition: Time for plasma drug concentration to fall by 50%
• Formula: t₁/₂ = 0.693 × Vd / CL
• After 4-5 half-lives: drug is ~97% eliminated (clinically considered fully excreted)
• After 4-5 half-lives of continuous dosing: drug reaches steady state
• Example: If t₁/₂ = 6 hrs → steady state reached in ~30 hrs

Clearance (CL):

• Definition: Volume of plasma cleared of drug per unit time (mL/min or L/hr)
• Determines maintenance dose
• Total CL = hepatic CL + renal CL + other CL

Steady-State Concentration (Css):

• Achieved when rate of drug input = rate of elimination
• Clinically important for dosing schedules

Linear vs. Non-Linear (Saturation) Kinetics:

Compartment Models:

• Body treated as a single homogeneous compartment
• Drug distributes instantly and uniformly
• Simpler; applies to drugs distributed mostly in plasma/extracellular fluid
• Log plasma concentration vs. time = straight line (monoexponential decline)

• Body = central compartment (plasma + highly perfused organs) + peripheral compartment (muscle, fat, skin)
• Drug first distributed to central, then slowly to peripheral
• Plasma concentration-time curve = biexponential decline (biphasic curve: alpha phase = distribution; beta phase = elimination)
• Most clinically used drugs follow this model

• More complex; three or more compartments
• Used for drugs with very complex distribution (e.g., some antibiotics, cytotoxic drugs)

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PART B: PHARMACODYNAMICS

Definition: Pharmacodynamics (PD) = "What the drug does to the body" Studies the mechanisms of drug action - how drugs produce their effects through molecular interactions.

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6. DRUG-RECEPTOR INTERACTIONS

What is a Receptor?

• Macromolecule (usually protein) on cell surface or inside cell that specifically recognizes and binds a drug or endogenous ligand
• Binding initiates a biochemical cascade → pharmacological effect

Families of Receptors (Structural Classification):

Receptor Theories:

1. Occupancy Theory (Clark): Drug effect is proportional to number of receptors occupied; maximum effect when all receptors occupied
2. Rate Theory (Paton): Effect is proportional to rate of drug-receptor association/dissociation (not just occupancy)
3. Induced-fit Theory: Drug binding changes receptor conformation to produce effect
4. Spare Receptor Theory: Maximum effect achievable even when only a fraction of receptors occupied; extra receptors = "spare" or "reserve" receptors (amplifies sensitivity)

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7. AGONISTS AND ANTAGONISTS

Agonist:

• Drug that binds receptor AND activates it → produces response
• Has both affinity (ability to bind) and intrinsic activity/efficacy (ability to activate)
• Full agonist: Produces maximum response (intrinsic activity = 1); e.g., adrenaline on β receptors
• Partial agonist: Binds receptor but produces less than maximum response even at full occupancy (intrinsic activity 0 < IA < 1); e.g., buprenorphine, pindolol
  • Can act as an ANTAGONIST in presence of a full agonist (competitive antagonism)
• Inverse agonist: Binds receptor and produces effect opposite to the agonist; e.g., some benzodiazepine site ligands

Antagonist:

• Drug that binds receptor but does NOT activate it (no intrinsic activity = 0)
• Blocks agonist from binding/acting

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8. DOSE-RESPONSE RELATIONSHIPS

Graded Dose-Response Curve:

• Shows increasing response of a single subject/tissue as dose increases
• Sigmoid (S-shaped) curve when plotted on log-scale

Key Parameters:

Key rule: Two drugs can have the same efficacy but different potency, OR same potency but different efficacy.

Quantal Dose-Response Curve:

• All-or-none response in a population (e.g., seizure occurs or not)
• Plots % of population responding vs. dose
• ED50: Dose effective in 50% of population
• LD50: Dose lethal in 50% of animals
• TD50: Toxic dose in 50% of population

Therapeutic Index (TI):

• TI = LD50 / ED50 (animal studies) or TD50 / ED50 (human studies)
• High TI = wide safety margin (safe drug) e.g., penicillin
• Low/Narrow TI = small safety margin (dangerous, monitor closely) e.g., digoxin, lithium, warfarin, phenytoin, aminoglycosides

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9. DRUG TOLERANCE, TACHYPHYLAXIS & RELATED TERMS

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PART C: GENERAL CONCEPTS

10. ESSENTIAL DRUGS & DRUG NOMENCLATURE

• Essential drugs (WHO): Minimum drugs needed to satisfy health care needs of a population; basis of rational drug policy
• Generic name (INN): International non-proprietary name; preferred for prescribing
• Brand name: Proprietary name given by manufacturer
• Rational Drug Use: Right drug, right dose, right route, right patient, right duration

11. SOURCES OF DRUGS

1. Plant sources - morphine (poppy), digoxin (Digitalis), atropine (Atropa belladonna), quinine (Cinchona)
2. Animal sources - insulin (pig/cow pancreas), heparin (porcine intestinal mucosa), vaccines
3. Mineral sources - iron, lithium, magnesium sulfate, zinc oxide
4. Synthetic/semisynthetic - majority of modern drugs; aspirin, paracetamol, sulfonamides
5. Recombinant DNA (Biotechnology) - human insulin, EPO, monoclonal antibodies, vaccines

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QUICK REVISION TABLES

Key Formulas at a Glance:

Mnemonics:

• ADME = Absorption, Distribution, Metabolism, Excretion
• GPCR types: Gs (stimulates adenylyl cyclase), Gi (inhibits), Gq (activates phospholipase C)
• Narrow TI drugs: "WILD" = Warfarin, Isoniazid, Lithium, Digoxin (+ phenytoin, aminoglycosides)
• Enzyme inducers: "PC BRAS" = Phenytoin, Carbamazepine, Barbiturates, Rifampicin, Alcohol (chronic), St. John's wort
• Enzyme inhibitors: "CAKE" = Cimetidine, Azole antifungals, Ketoconazole, Erythromycin (+grapefruit juice)

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IMPORTANT EXAM POINTS (Short Answer Ready):

1. Bioavailability = 100% only for IV route
2. First-pass effect - oral drugs undergo this in liver; bypass with sublingual/IV
3. Only free drug is active, filterable, and metabolizable (protein-bound drug = inactive reservoir)
4. Phase I = functionalization (oxidation/reduction/hydrolysis via CYP450); Phase II = conjugation
5. Rifampicin is the classic enzyme inducer (decreases efficacy of many drugs including OCP)
6. Competitive antagonism = parallel right shift of dose-response curve (Emax unchanged)
7. Non-competitive antagonism = depresses Emax (ceiling effect lowered)
8. Partial agonist has efficacy between 0-1; acts as antagonist in presence of full agonist
9. Narrow therapeutic index drugs require therapeutic drug monitoring (TDM)
10. Two-compartment model = alpha phase (distribution) + beta phase (elimination)

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