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📘 BPT 2nd Year - General Pharmacology Notes

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UNIT 1: PHARMACOKINETICS

"Pharmacokinetics refers to what the body does to a drug."

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CHAPTER 1: PHARMACOKINETICS

I. Routes of Drug Administration

A. Enteral Routes

B. Parenteral Routes

C. Topical/Other Routes

• Topical: Local effect on skin/mucosa
• Transdermal patch: Systemic effect via skin absorption; rate depends on skin characteristics and drug lipid solubility; e.g., nicotine patch, fentanyl patch
• Inhalation: Rapid absorption; used for respiratory diseases (asthma, COPD); minimizes systemic effects
• Rectal: 50% bypasses portal circulation; useful when oral route not feasible (vomiting, unconscious patient); absorption is often erratic

Clinical relevance for physiotherapy: Transdermal patches (e.g., diclofenac, fentanyl) and topical NSAIDs are commonly used in patients you will encounter in musculoskeletal and palliative care settings.

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II. Drug Absorption

Bioavailability (F)

• The fraction of administered drug that reaches systemic circulation unchanged
• IV administration = 100% bioavailability (F = 1.0)
• Oral bioavailability is often less than 100% due to:
  1. Incomplete absorption
  2. First-pass effect - drug is metabolized in the gut wall and liver before reaching systemic circulation

First-Pass Effect (Presystemic Metabolism)

• Oral drugs absorbed from GI tract pass through the portal vein --> liver --> general circulation
• The liver may extensively metabolize a drug before it reaches systemic circulation
• Drugs with high first-pass effect (e.g., morphine, propranolol, nitroglycerin) may need higher oral doses or alternative routes
• Sublingual/rectal routes bypass the liver and avoid first-pass effect

Factors Affecting Absorption

1. Blood flow - Greater blood flow at absorption site = faster absorption
2. Surface area - Small intestine has a large surface area (villi, microvilli) = main absorption site
3. Drug ionization (pH-partition theory)
   • Most drugs are weak acids or weak bases
   • Only the non-ionized (uncharged) form crosses lipid membranes easily
   • Weak acids (e.g., aspirin, pKa 3.5) are better absorbed in the acidic stomach (non-ionized form predominates in acid)
   • Weak bases (e.g., morphine, pKa 8) are better absorbed in the alkaline intestine
   • Henderson-Hasselbalch equation applies: pH = pKa + log [ionized/non-ionized] for acids
4. Solubility - Drugs must dissolve before absorption; highly lipid-soluble drugs cross membranes easily
5. Drug formulation - Particle size, salt form, enteric coatings all affect dissolution and absorption rate
6. Chemical instability - Penicillin G is unstable in gastric acid; insulin is destroyed by GI enzymes

Bioequivalence

• Two formulations are bioequivalent if they show comparable bioavailability and similar times to reach peak blood concentrations
• Therapeutic equivalence requires bioequivalence + pharmaceutical equivalence (same dosage form, same active ingredient, same route)

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III. Drug Distribution

Factors Affecting Distribution

1. Blood flow - High blood flow to "vessel-rich organs" (brain, liver, kidney) leads to rapid drug uptake. Skeletal muscle, adipose tissue get less blood flow.
2. Capillary permeability
   • Liver and spleen: large, discontinuous capillaries - large molecules can pass
   • Brain: tight junctions form the blood-brain barrier (BBB) - only lipid-soluble drugs or actively transported drugs penetrate
   • Example: Levodopa uses a specific transporter to enter the brain
3. Plasma protein binding
   • Many drugs bind to plasma proteins (mainly albumin)
   • Only the free (unbound) drug is pharmacologically active and can distribute into tissues
   • Drug binding is reversible; bound drug acts as a reservoir
   • Drugs that are highly protein-bound (e.g., warfarin, valproic acid) can be displaced by other drugs --> dangerous interactions
   • In hypoalbuminemia, free drug concentration increases --> risk of toxicity
4. Tissue binding
   • Some drugs accumulate in tissues (bone, fat, muscle) acting as reservoirs
   • Fat-soluble drugs (e.g., diazepam) accumulate in adipose tissue

Volume of Distribution (Vd)

Vd = Dose / Plasma concentration

• Vd is an apparent (not real) volume
• Low Vd (close to plasma volume ~3-5L): Drug stays in vascular compartment (e.g., heparin, large molecules or highly protein-bound drugs)
• High Vd (hundreds of liters): Drug distributes extensively into tissues (e.g., chloroquine, digoxin)
• Vd formula: Vd = Loading Dose / (Cp × F) or rearranged: Loading Dose = Vd × Cp / F

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IV. Drug Metabolism (Biotransformation)

• Primary site: Liver (also GI tract, kidneys, lungs)
• Goals: Convert lipophilic drugs to hydrophilic (water-soluble) metabolites for renal excretion
• Metabolism may: increase, decrease, or have NO effect on pharmacologic activity
• Prodrugs are inactive drugs that become active after metabolism (e.g., codeine --> morphine via CYP2D6; clopidogrel --> active metabolite via CYP2C19)

Phase I Reactions (Functionalization)

• Add or unmask a polar functional group (-OH, -NH2, -SH)
• Types: Oxidation, Reduction, Hydrolysis
• Most common: Cytochrome P450 (CYP) enzyme system (located mainly in liver and GI tract)

• CYP2D6: Poor metabolizers can't activate codeine (no analgesia); Ultra-rapid metabolizers convert codeine to morphine rapidly (toxic levels in breastfed infants)
• CYP2C19: Poor metabolizers get reduced antiplatelet effect from clopidogrel
• This forms the basis of pharmacogenomics - personalizing drug therapy based on genetic makeup

Phase II Reactions (Conjugation)

• Phase I metabolite conjugated with an endogenous substrate
• Types: Glucuronidation (most common), sulfation, acetylation, methylation, amino acid conjugation
• Generally inactivates drugs and increases water solubility for excretion

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V. Drug Elimination (Excretion)

1. Glomerular filtration (free drug is filtered; protein-bound drug is NOT)
2. Active tubular secretion
3. Passive tubular reabsorption

Clinical note: Patients with renal dysfunction cannot excrete drugs efficiently -> drug accumulation -> toxicity. Dose reduction is required.

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VI. Pharmacokinetic Parameters

Half-Life (t½)

• Time for plasma drug concentration to fall by 50%
• t½ = 0.693 × Vd / Clearance
• Used to determine dosing intervals
• ~4-5 half-lives to reach steady state and ~4-5 half-lives to eliminate a drug from the body

Clearance (CL)

• Volume of plasma cleared of drug per unit time (L/hr or mL/min)
• CL = Rate of elimination / Plasma concentration
• Hepatic + Renal clearance are the main components

Steady State (Css)

• Plasma concentration at which rate of drug input = rate of elimination
• Achieved after ~4-5 half-lives of repeated dosing
• If dose is doubled, Css doubles (linear kinetics)

Loading Dose vs. Maintenance Dose

Loading doses are used when rapid onset is needed (e.g., digoxin, loading antibiotics in sepsis).

Zero-Order vs. First-Order Kinetics

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CHAPTER 2: PHARMACODYNAMICS

"Pharmacodynamics describes what the drug does to the body."

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I. Receptors and Signal Transduction

• Most drugs exert effects by interacting with specialized target macromolecules called receptors
• The drug-receptor complex initiates signal transduction - a cascade of biochemical events producing cellular response
• The magnitude of response is proportional to the number of drug-receptor complexes formed

Types of Drug Receptors

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II. Agonists and Antagonists

Agonists

• Drugs that bind to a receptor AND activate it to produce a response
• Full agonist: Produces maximum possible response (100% efficacy)
• Partial agonist: Produces less than maximum response even at full receptor occupancy; can act as antagonist when competing with a full agonist
  • Example: Buprenorphine (partial opioid agonist)

Antagonists

• Drugs that bind to a receptor but do NOT activate it; they block agonists from binding
• Have high affinity but zero/low efficacy

• Antagonist competes with agonist for the same receptor binding site
• Effect is reversible by increasing agonist concentration
• Shifts the dose-response curve to the right (parallel shift; same maximum, higher EC50)
• Example: Atropine blocks acetylcholine at muscarinic receptors

• Antagonist binds irreversibly or at an allosteric site; cannot be overcome by increasing agonist
• Reduces the maximum response (Emax decreases); shifts curve downward
• Example: Phenoxybenzamine (irreversible alpha-blocker)

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III. Dose-Response Relationships

Graded Dose-Response Curve

• As dose increases, response increases up to a maximum
• Plotted as log dose vs. effect (produces a sigmoid/S-shaped curve)

• EC50 (ED50): Dose producing 50% of maximum effect - measures potency
• Emax: Maximum effect achievable - measures efficacy

• Potency = how much drug is needed to produce an effect (lower EC50 = more potent)
• Efficacy = maximum effect a drug can produce
• A drug can be highly potent but have low efficacy (e.g., partial agonist) or vice versa
• Clinically, efficacy matters more than potency

Therapeutic Index (TI) / Safety Window

TI = TD50 / ED50 (or LD50 / ED50 in animals)

• TD50: Dose producing toxicity in 50% of population
• ED50: Dose producing therapeutic effect in 50% of population
• High TI = safer drug (e.g., penicillin); Low TI = narrow safety margin (e.g., digoxin, warfarin, lithium, theophylline)
• Drugs with narrow therapeutic index require therapeutic drug monitoring (TDM)

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IV. Drug Tolerance and Tachyphylaxis

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V. Drug Interactions

Pharmacokinetic Interactions

• One drug affects the ADME of another
• Examples:
  • CYP inducers (rifampicin) reduce levels of co-administered drugs
  • CYP inhibitors (erythromycin) increase levels of co-administered drugs
  • Antacids reduce absorption of certain antibiotics (tetracycline chelation)

Pharmacodynamic Interactions

• Drugs interact at the receptor or physiological level

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VI. Special Pharmacokinetic Considerations

Factors That Alter Drug Response

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QUICK REVIEW: KEY TERMS TABLE

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DIAGRAMS TO KNOW

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IMPORTANT EXAM POINTS FOR BPT

1. ADME - the four pharmacokinetic processes; know them in order
2. First-pass effect - why nitroglycerin is given sublingually (not orally)
3. Ion-trapping - weak acids are absorbed better in the stomach; weak bases in the intestine
4. Protein binding - only FREE drug is active; low albumin -> higher free drug -> toxicity risk
5. CYP3A4 is the most important drug-metabolizing enzyme; know key inducers and inhibitors
6. Half-life determines dosing frequency; 4-5 half-lives to reach steady state
7. Narrow therapeutic index drugs (digoxin, warfarin, lithium, theophylline) require monitoring
8. Agonist vs. Antagonist - know the types and examples
9. Therapeutic index formula: TI = TD50/ED50
10. Competitive antagonism shifts dose-response curve to the right without changing Emax; non-competitive reduces Emax

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