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GENERAL PHARMACOLOGY

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1. DEFINITIONS

• Chemical name - describes chemical structure (e.g., acetylsalicylic acid)
• Generic/Nonproprietary name (INN) - universal scientific name (e.g., aspirin)
• Brand/Proprietary name - manufacturer's name (e.g., Disprin, Ecosprin)

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2. SOURCES OF DRUGS

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3. ROUTES OF DRUG ADMINISTRATION

A. Enteral (Oral)

• Most common, oldest, safest route
• Advantages: Safe, convenient, economical, self-administered, non-invasive
• Disadvantages: Slow onset, cannot give to unconscious patients, some drugs destroyed by gastric juice (insulin), extensive first-pass metabolism

• Enteric coated tablets - coated with cellulose-acetate phthalate; dissolve in alkaline intestinal juice, not stomach; prevent gastric irritation
• Sustained-release preparations - prolong absorption and duration of action; reduce dosing frequency

B. Parenteral Routes

C. Inhalation

• Gases, volatile liquids (general anaesthetics), aerosols (salbutamol)
• Almost instantaneous absorption (large lung surface area)
• Avoids first-pass metabolism
• Useful for pulmonary diseases (drug delivered at site)

D. Transdermal

• Lipid-soluble drugs; slow, prolonged absorption
• Patches (fentanyl, nitroglycerin, hyoscine, scopolamine); constant plasma levels; good compliance

E. Transmucosal

• Sublingual - under tongue; rapid absorption; bypasses first-pass metabolism; e.g., nitroglycerine, nifedipine, buprenorphine
• Nasal - systemic (oxytocin spray) or local (oxymetazoline decongestant, budesonide)
• Rectal - useful in vomiting/unconscious; absorption may be irregular

F. Topical

• Local action on skin/mucous membranes (creams, ointments, drops, pessaries)

Special Drug Delivery Systems

• Prodrug - inactive form converted to active drug in body (e.g., levodopa → dopamine; enalapril → enalaprilat)
• Liposomes - phospholipid vesicles that target RES cells and tumors
• Ocusert - pilocarpine reservoir under eyelid; releases drug for 7 days
• Osmotic pumps - constant release (iron, prazosin)
• Computerized pumps - programmed continuous (insulin) or pulsatile (GnRH) release

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4. PHARMACOKINETICS (ADME)

A. Absorption

• Passive diffusion - down concentration gradient; no energy; most common
• Filtration - through aqueous pores; small water-soluble molecules
• Active transport - against gradient; energy required; carrier-mediated; e.g., levodopa, iron, amino acids
• Facilitated diffusion - carrier-mediated but no energy; e.g., glucose, vitamin B12
• Endocytosis - engulfment of droplets; some proteins

1. Disintegration and dissolution time
2. Formulation (excipients)
3. Particle size (smaller = better absorption; exception: anthelmintics)
4. Lipid solubility (higher = better absorption)
5. pH and ionization - Ionized drugs poorly absorbed; un-ionized = lipid soluble = well absorbed
   • Acidic drugs (aspirin, barbiturates) - absorbed from acidic stomach
   • Basic drugs (pethidine, ephedrine) - absorbed from alkaline intestine
6. Area and vascularity of absorbing surface (small intestine - large area + high vascularity)
7. GI motility - faster gastric emptying = faster absorption; diarrhea = reduced absorption
8. Food - delays absorption; some drugs need empty stomach (ampicillin, rifampicin)
9. Gut metabolism - some drugs degraded in GI tract (nitroglycerin, insulin)
10. Gut diseases (malabsorption, achlorhydria)

• Metabolism of drug during first passage through gut wall and liver
• Reduces bioavailability
• Examples: nitroglycerin, propranolol, morphine, verapamil, testosterone, insulin, lignocaine
• If partial: increase oral dose (propranolol)
• If extensive: change route (insulin → parenteral)

• IV = 100%; SC/IM ≈ 100%; Oral = variable (affected by absorption + first-pass)

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B. Distribution

• Acidic drugs bind albumin; basic drugs bind alpha-1-acid glycoprotein
• Only free (unbound) fraction is pharmacologically active, metabolized, excreted
• Bound drug = reservoir; prolongs duration of action
• Drug displacement interactions (e.g., indomethacin displaces warfarin → toxicity)
• Hypoalbuminemia (renal/liver failure) → increased free drug → toxicity risk

• Large Vd (e.g., pethidine) = drug is sequestered in tissues; NOT removable by hemodialysis

• Brain capillary endothelial cells have tight junctions + glial cell covering
• Only lipid-soluble, un-ionized drugs cross normally
• Inflammation (meningitis) increases permeability - penicillin can enter
• Weak areas: CTZ, posterior pituitary, parts of hypothalamus

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C. Biotransformation (Metabolism)

• Oxidation, reduction, hydrolysis
• Catalyzed by microsomal enzymes (cytochrome P450)
• Makes drug more polar

• Glucuronide conjugation (most common), acetylation, methylation, glutathione, sulfate conjugation
• Produces highly polar, inactive compound → excreted by kidneys
• Always inactivates the drug

• Certain drugs ↑ synthesis of microsomal enzymes → faster metabolism of inducing drug + other drugs
• Inducers: Phenobarbitone, rifampicin, alcohol, cigarette smoke, DDT, carbamazepine, phenytoin, griseofulvin
• Clinical use: Phenobarbitone given to neonates with jaundice to enhance bilirubin conjugation
• Drug interaction: Rifampicin induces metabolism of oral contraceptives → contraceptive failure

• Inhibitors: Cimetidine, ketoconazole, chloramphenicol, erythromycin, ciprofloxacin, verapamil
• Result: Reduced metabolism of other drugs → toxicity

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D. Excretion

1. Glomerular filtration - depends on GFR, free drug concentration, molecular weight (<10,000); ionized drugs of low MW filtered freely
2. Active tubular secretion - proximal tubule; acids (penicillin, salicylic acid, frusemide, probenecid) and bases (amphetamine, histamine) secreted separately
   • Drug competition: penicillin + probenecid compete for same carrier → probenecid prolongs penicillin action
3. Passive tubular reabsorption - lipid-soluble drugs reabsorbed (slower excretion)
   • Clinical application in poisoning:
     • Acidic drug poisoning (salicylates, barbiturates) → forced alkaline diuresis (diuretic + NaHCO3 + IV fluids) → drug ionizes in alkaline urine → excreted faster
     • Basic drug poisoning (quinine, amphetamine) → forced acid diuresis

• Enterohepatic circulation - drug reabsorbed from gut → back to liver → prolonged duration of action
• Examples: Chloramphenicol, tetracycline, oral contraceptives, erythromycin

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E. Kinetics of Elimination

• 4-5 half-lives to completely eliminate a drug
• 4-5 half-lives to reach steady state on repeated dosing
• Guides dosing interval and frequency

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5. PHARMACODYNAMICS

A. How Drugs Act

B. Mechanisms of Drug Action

1. Through Receptors (most common mechanism)
2. Enzyme inhibition - allopurinol inhibits xanthine oxidase; acetazolamide inhibits carbonic anhydrase; omeprazole inhibits H+/K+ ATPase; neostigmine inhibits acetylcholinesterase
3. Ion channels - calcium channel blockers (amlodipine); potassium channel openers (minoxidil)
4. Physical action - activated charcoal (adsorption); bulk laxatives (mass); mannitol (osmosis); 131I (radioactivity); barium sulphate (radio-opacity)
5. Chemical interaction - antacids neutralize acid; chelating agents bind heavy metals; KMnO4 oxidizes
6. Altering metabolic processes - sulfonamides block bacterial folic acid synthesis

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C. Receptors

• Affinity - ability of a drug to bind to a receptor
• Intrinsic activity (Efficacy) - ability to produce a response after binding
• Ligand - any molecule that binds selectively to a receptor

1. Ion channel-linked receptors - Nicotinic ACh receptor; GABA-A receptor
2. G-protein coupled receptors (GPCR) - Adrenergic, muscarinic, opioid receptors; act via second messengers (cAMP, IP3)
3. Enzyme-linked receptors (Tyrosine kinase) - Insulin receptor; growth factor receptors
4. Nuclear receptors - Steroid hormones, thyroid hormones; regulate gene transcription

• Up-regulation - prolonged antagonist use or agonist deprivation → ↑ receptor number and sensitivity. Example: Propranolol (β-blocker) use → up-regulation of β receptors. Sudden withdrawal → precipitation of angina
• Down-regulation - prolonged agonist stimulation → ↓ receptor number (desensitization). Example: Chronic salbutamol use in asthma → ↓ β2 receptor response

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D. Dose-Response Relationship

• Response increases with dose until maximum effect reached
• Log dose vs. response = sigmoid (S-shaped) curve

• Lower dose needed = more potent
• Example: Bumetanide 1 mg = frusemide 50 mg in diuresis; bumetanide is more potent

• Clinically more important than potency

• Higher TI = safer drug
• Penicillin: High TI | Lithium, digoxin: Low TI
• Drugs with low TI require therapeutic drug monitoring (TDM)

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E. Drug Synergism and Antagonism

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6. FACTORS MODIFYING DRUG EFFECTS

Tolerance and Tachyphylaxis

• Natural tolerance: Species/race-based (rabbits to atropine)
• Acquired tolerance: On repeated use (barbiturates, opioids, nitrites)
• Pharmacokinetic (Dispositional) tolerance: ↑ drug metabolism (barbiturates induce their own metabolism)
• Pharmacodynamic (Functional) tolerance: Down-regulation of receptors (opioids)
• Cross tolerance: Tolerance extends to pharmacologically related drugs (alcohol → barbiturates → anaesthetics)

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7. ADVERSE DRUG REACTIONS (ADRs)

• Conception to day 16 → usually resistant; if affected → abortion
• Day 17-55 (organogenesis) → most vulnerable; major physical abnormalities
• Day 56 onwards → developmental and functional abnormalities

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8. DRUG INTERACTIONS

• In vitro (in syringe): Penicillin + gentamicin should never be mixed
• In vivo (in body): After administration

Pharmacokinetic Drug Interactions

Pharmacodynamic Drug Interactions

• Same receptor/physiological system → additive/synergistic/antagonistic effects
• Atropine opposes physostigmine; naloxone antagonizes morphine
• β-blockers' antihypertensive effect reduced by vasoconstrictors (ephedrine in cold remedies)

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9. GENE THERAPY

• Replacement of defective gene with a functional gene
• Unlike all other drugs that modify rate of cell functions, gene therapy can confer new functions to the cell
• Vectors for gene transfer: Viral vectors (retroviral, adenoviral) and liposomes
• Applications: Cancer, cardiovascular disease, AIDS/immunodeficiency, anemia, Alzheimer's disease, inherited single-gene disorders

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Quick Reference: Methods to Prolong Drug Action

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