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📘 General Pharmacology — Easy English Notes

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PART 1: PHARMACOKINETICS

"What the body does to the drug"

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🕐 Plasma Half-Life (t½)

• Alpha (α) phase — Drug drops fast at first → because it is spreading (distributing) into body tissues
• Beta (β) phase — Drug drops slowly later → because it is being eliminated (removed) from body

t½ = 0.693 × Vd ÷ CL

• Vd = Volume of distribution (how widely drug spreads in body)
• CL = Clearance (how fast body removes the drug)

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📉 First Order vs Zero Order Kinetics

First Order Kinetics

• A fixed percentage of drug is removed per unit time (not a fixed amount)
• t½ stays constant no matter what dose you give
• How much drug is eliminated with each half-life:

Zero Order Kinetics

• A fixed amount of drug is removed per unit time
• As dose increases → clearance cannot keep up → t½ increases
• Example: Alcohol, aspirin at high doses

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💊 Repeated Drug Administration — Plateau Principle

✅ Steady state is reached in 4–5 half-lives

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🧮 Dose Rate and Maintenance Dose Formulas

• Dose Rate = Target Cpss × Clearance (÷ F if given orally; F = bioavailability)
• Maintenance Dose = Dose Rate × Dose Interval

• Target level = 20 mg/L, CL = 2.8 L/hr, Vd = 35 L, given orally every 12 hours
• Dose rate = 2.8 × 20 = 56 mg/hour
• Maintenance dose = 56 × 12 = 700 mg every 12 hours
• Half-life = 0.7 × 35 ÷ 2.8 = ~8.75 hours

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🎯 Target Level Strategy

Drugs with SHORT t½ (up to 2–3 hours)

• Steady state reached quickly (within hours) → clinically OK
• Can be given at regular intervals (every 6–12 hours)

Drugs with LONG t½

• Steady state would take days to reach → clinically unacceptable (too slow)
• Solution: Use Loading Dose + Maintenance Dose

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⚡ Loading Dose vs Maintenance Dose

Think of it like filling a bucket quickly (loading), then dripping water in to keep it full (maintenance).

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🔬 Therapeutic Drug Monitoring (TDM)

✅ TDM IS needed for:

1. Drugs with narrow safety margin (small gap between effective and toxic dose): Digoxin, anticonvulsants, theophylline, lithium, aminoglycosides, tricyclic antidepressants
2. Toxic drugs used in patients with kidney failure: Aminoglycosides, vancomycin
3. Poisoning cases
4. Treatment failure without a clear reason (e.g., antibiotics not working — is patient absorbing them?)
5. Checking if patient is taking the drug (compliance monitoring): Psychiatric drugs

❌ TDM is NOT needed for:

1. Drugs where you can directly measure the effect: Antihypertensives (check BP), diuretics (check urine output), blood sugar drugs
2. Drugs that are activated inside the body (prodrugs): Levodopa
3. "Hit and run" drugs that work long after they leave the blood: Reserpine, MAO inhibitors, omeprazole
4. Drugs with irreversible action: Organophosphates, phenoxybenzamine

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PART 2: PHARMACODYNAMICS

"What the drug does to the body"

Key principle: Drugs don't create new functions. They only modify what the body already does.

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🔧 Types of Drug Actions

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⚙️ Mechanisms of Drug Action (4 Types)

1. Enzymes
2. Ion channels
3. Transporters
4. Receptors

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1. 🧪 Enzymes

• Active site — where the actual chemical work happens (substrate binds here)
• Allosteric site — a different site where drugs can bind and indirectly change the enzyme's behavior

Michaelis-Menten Model (simple idea):

• As you add more substrate → reaction speed increases
• But there's a maximum speed the enzyme can work at (Vmax)
• Km = the amount of substrate needed to reach half of Vmax (measures enzyme's "hunger" for substrate — lower Km = higher affinity)

Drugs can either INCREASE or DECREASE enzyme activity:

⬆️ Increase Enzyme Activity:

⬇️ Decrease Enzyme Activity (Enzyme Inhibition):

A) Competitive Inhibition

• Inhibitor looks like the substrate → competes for the active site

Think: reversible competitor blocks the door but you can push it out by flooding with substrate. Irreversible competitor is glued to the door.

B) Non-Competitive Inhibition

• Inhibitor binds to the allosteric site (not the active site)
• Changes the shape of the enzyme so it can't work properly
• Cannot be overcome by adding more substrate

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2. 🎯 Receptors

Drug binds to receptor (Affinity) → Activates receptor (Intrinsic Activity) → Signal is sent (Transduction) → Effect happens

Two Key Properties:

• Affinity = How well the drug sticks to the receptor. High affinity = works at low doses
• Intrinsic Activity (IA) = How much the drug activates the receptor after binding (scale: −1 to +1)

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🧬 Types of Drugs Based on Intrinsic Activity:

Antagonist = blocks the receptor so the body's own chemical (agonist) can't work. Like a key that fits the lock but won't turn it — and prevents the real key from entering.

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📡 Transducer Mechanisms — 5 Types of Receptors

1. G-Protein Coupled Receptors (GPCR)

• Has 7 helical segments spanning the cell membrane
• Has 3 subunits: α, β, γ
• In resting state: GDP is attached to α subunit
• When drug activates: GDP is replaced by GTP → α subunit separates → causes effects

A) Adenylate Cyclase / cAMP Pathway

Drug → activates Gs → activates adenylyl cyclase → ATP becomes cAMP → activates protein kinase → phosphorylates enzymes & ion channels → Effect

• Like a chain of dominoes that ends in cell changes

B) Phospholipase C: IP3-DAG Pathway

Drug → activates Gs → activates Phospholipase C → breaks PIP2 into IP3 + DAG

• IP3 → releases Calcium (Ca²⁺) from inside cell → effect
• DAG → activates Protein Kinase C → effect

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2. Ion Channel Receptors (Ligand-Gated Ion Channels)

• The receptor IS the ion channel itself
• When drug binds → gate opens → ions (Na⁺, K⁺, Ca²⁺, or Cl⁻) flow in/out
• Changes electrical charge across the membrane → depolarization or hyperpolarization
• Fastest acting receptor type
• Example: Nicotinic acetylcholine receptor, GABA receptor

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3. Transmembrane Enzyme-Linked Receptors

• Drug binds on outside of cell → activates enzyme (tyrosine kinase) on the inside
• Two receptor molecules come together (dimerize) → activate each other → signal travels into cell
• Example: Insulin receptor, growth factor receptors

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4. JAK-STAT Receptors

• Drug binds → receptor dimerizes → recruits free-floating JAK (Janus Kinase) molecules
• JAK activates STAT proteins → STATs move into the nucleus → change which genes are turned on
• Used by cytokines, interferons, growth hormone
• Slower than ion channels, faster than nuclear receptors

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5. Receptors Regulating Gene Expression (Nuclear/Transcription Factor Receptors)

• These receptors are inside the cell (not on the surface)
• Only lipid-soluble (fat-soluble) drugs can enter the cell to reach them — e.g., steroids, thyroid hormones
• In resting state: receptor is bound to Heat Shock Proteins (HSP 90, HSP 70) in the cytoplasm

Steroid enters cell → binds receptor → HSP proteins fall off → receptor dimerizes → moves into nucleus → binds DNA → changes gene transcription → new proteins made → Effect

• Slowest acting receptor (hours to days)
• Effects last very long because new proteins are made
• Example: Glucocorticoid receptors, sex hormone receptors

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🗂️ Quick Summary Table — Receptor Types

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