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General Pharmacy - BDS Students

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1. Definition of Pharmacology

• Pharmacokinetics - what the body does to the drug (absorption, distribution, metabolism, elimination - ADME)
• Pharmacodynamics - what the drug does to the body (mechanism of action, receptor interactions)
• Toxicology - the branch dealing with undesirable effects of chemicals on living systems

"Pharmacokinetics refers to what the body does to a drug, whereas pharmacodynamics describes what the drug does to the body." - Lippincott Illustrated Reviews: Pharmacology

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2. Drug Sources and Properties

Sources of Drugs

Drug Size

Drug-Receptor Bonds

1. Covalent bonds - very strong, often irreversible (e.g., aspirin irreversibly acetylates cyclooxygenase - this is why aspirin's antiplatelet effect lasts days)
2. Electrostatic bonds - most common; includes ionic bonds, hydrogen bonds, and van der Waals forces
3. Hydrophobic bonds - weak; important for lipid-soluble drugs at cell membranes

Drugs binding through weak bonds are generally more selective because they require a very precise fit to their receptor.

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3. Routes of Drug Administration

A. Enteral (via GI tract)

B. Parenteral (bypasses GI tract)

C. Topical/Local

• Applied directly to skin or mucous membranes
• Advantages: Localized action, minimal systemic side effects
• Dental relevance: Topical anesthetics (benzocaine gel), chlorhexidine mouthwash, antifungal oral gels

D. Inhalation

• Rapid absorption via large alveolar surface area
• Used for: General anesthetics (nitrous oxide in dentistry), bronchodilators

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4. Pharmacokinetics - ADME

A. Absorption

Mechanisms of Drug Transport Across Membranes

1. Passive diffusion - most common mechanism; drug moves from high to low concentration; no carrier required; not saturable; lipid-soluble drugs cross most membranes easily
2. Facilitated diffusion - carrier-mediated; no energy required; can be saturated; competitive inhibition possible
3. Active transport - carrier-mediated; energy (ATP) dependent; moves drug against concentration gradient; saturable and selective
4. Endocytosis - for very large molecules (e.g., Vitamin B12 absorbed via endocytosis in gut wall)

Effect of pH on Drug Absorption (Henderson-Hasselbalch)

• Most drugs are weak acids or weak bases
• Uncharged (un-ionized) form penetrates cell membranes readily
• For weak acids (e.g., aspirin, penicillin): un-ionized in acidic environment - better absorbed in stomach
• For weak bases (e.g., morphine, local anesthetics like lidocaine): un-ionized in alkaline environment - better absorbed in intestine
• pKa: lower pKa = more acidic drug; higher pKa = more basic drug

Clinical pearl for BDS: Local anesthetics (weak bases, pKa ~7.8-9.0) work poorly in infected tissues because the acidic environment of infection keeps them ionized, reducing penetration to nerve membranes. This is why dental blocks can fail in acute dental abscesses.

Bioavailability

• Definition: Fraction of administered drug that reaches systemic circulation unchanged
• IV route = 100% bioavailability
• Oral bioavailability is reduced by: first-pass metabolism, poor GI absorption
• First-pass (hepatic) effect: Drug absorbed from GI tract passes through portal vein to liver before reaching systemic circulation. Extensive hepatic metabolism here reduces bioavailability (e.g., lidocaine has very high first-pass effect, which is why it cannot be given orally as an antiarrhythmic - relevant in dentistry when considering systemic effects of injected lidocaine)

B. Distribution

Factors Affecting Distribution

1. Plasma protein binding
   • Albumin is the major drug-binding protein
   • Only free (unbound) drug is pharmacologically active and can cross membranes
   • Bound drug = inactive reservoir; dissociates as free drug is eliminated
   • Drug interactions occur when two drugs compete for the same plasma protein binding sites
2. Tissue binding
   • Some drugs accumulate in tissues (higher tissue than plasma concentration)
   • Tissue reservoirs can prolong drug action
3. Lipophilicity
   • Lipophilic drugs cross cell membranes freely; distribution governed mainly by blood flow
   • Hydrophilic drugs pass through slit junctions only; confined to extracellular space
4. Blood-Brain Barrier (BBB)
   • Tight junctions of brain capillaries limit entry of hydrophilic drugs
   • Lipophilic drugs and those that are substrates for transport proteins cross more readily

Volume of Distribution (Vd)

• A large Vd = extensive tissue distribution
• A small Vd = confined to plasma

C. Metabolism (Biotransformation)

Phase I Reactions - "Functionalization"

• Add or expose a functional group (-OH, -NH₂, -SH, -COOH)
• Main system: Cytochrome P450 (CYP450) enzyme system in liver microsomes
• Products may be active, inactive, or toxic

Dental relevance: Ketoconazole (antifungal used in oral candidiasis) inhibits CYP3A4, increasing concentrations of many co-administered drugs including some antihistamines and corticosteroids. Erythromycin also inhibits CYP3A4.

Phase II Reactions - "Conjugation"

• Attach (conjugate) polar molecule to drug or Phase I metabolite
• Common conjugates: Glucuronic acid (most common), sulfate, acetyl group, amino acid
• Result: Polar, water-soluble, typically inactive metabolite excreted in urine or bile
• Exception: Morphine-6-glucuronide is MORE potent than morphine

• Some drugs increase CYP enzyme synthesis (e.g., rifampin, phenobarbital, phenytoin, carbamazepine)
• Result: Faster metabolism of co-administered drugs, reducing their plasma levels
• Example: A patient on carbamazepine (for trigeminal neuralgia) will metabolize many drugs faster

• Some drugs decrease CYP activity
• Result: Increased plasma concentration of co-administered drugs - risk of toxicity
• Important inhibitors: Ketoconazole, clarithromycin, ritonavir (each inhibit multiple CYP isozymes)

D. Elimination (Excretion)

Renal Excretion

1. Glomerular filtration - free (unbound) drug is filtered; protein-bound drug is not
2. Active tubular secretion - active transport into tubular lumen; handles both free and protein-bound drug
3. Passive tubular reabsorption - un-ionized/lipophilic drugs are reabsorbed back; ion trapping can promote excretion

This explains why sodium bicarbonate is given in aspirin overdose (as in the Katzung case study opening).

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5. Key Pharmacokinetic Parameters

Half-Life (t½)

• Time required for plasma drug concentration to fall by 50%
• t½ = 0.693 × Vd / Clearance
• After 4-5 half-lives: drug is ~94-97% eliminated (clinically considered eliminated)
• Steady state is reached after approximately 4-5 half-lives of repeated dosing
• 90% of steady state is achieved in 3.3 half-lives

Clearance (CL)

• Volume of plasma cleared of drug per unit time
• CL = Vd × 0.693 / t½

Steady State

• Plasma concentration at which the rate of drug administration equals the rate of elimination
• Loading dose can be used to achieve steady state rapidly (important in emergencies)

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6. Pharmacodynamics - Mechanisms of Drug Action

Drug Receptors

1. Selectively bind specific ligands (selectivity)
2. Change function upon binding to alter biologic system activity

Types of Receptors

Drug-Receptor Interactions

Dose-Response Relationships

• Efficacy (Emax): Maximum response a drug can produce
• Potency: Amount of drug needed to produce a given effect (usually ED50 - dose producing 50% of max effect)
• A drug can be potent but low efficacy, or vice versa

Therapeutic Index (TI)

• TD50 = dose causing toxicity in 50% of subjects
• ED50 = dose effective in 50% of subjects
• Narrow TI drugs (e.g., digoxin, lithium, warfarin, aminoglycosides, phenytoin) require careful dose titration and plasma monitoring

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7. Adverse Drug Reactions (ADRs)

• Immune-mediated reaction (Type B ADR)
• Types: IgE-mediated (anaphylaxis), cytotoxic (Type II), immune complex (Type III), T-cell mediated (Type IV)
• Dental relevance: Penicillin and local anesthetics (especially esters like procaine) can cause allergic reactions; always take drug allergy history before prescribing

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8. Drug Interactions

Pharmacokinetic Interactions

1. Absorption: Antacids chelate tetracyclines; reduce absorption
2. Metabolism: Enzyme inducers (rifampin) reduce efficacy; inhibitors (ketoconazole) increase toxicity
3. Protein binding displacement: One drug displaces another from albumin, increasing free drug levels (e.g., NSAIDs + warfarin)
4. Excretion: Probenecid blocks tubular secretion of penicillin (used therapeutically to prolong penicillin effect)

Pharmacodynamic Interactions

1. Synergism: Two drugs with similar effects - additive or supraadditive response
2. Antagonism: One drug diminishes effect of another (e.g., naloxone reverses opioid effect)

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9. Special Topics Relevant to Dentistry

Local Anesthetics (Dental Pharmacology Application)

• All commonly used dental local anesthetics are amide-linked (lidocaine, mepivacaine, articaine, bupivacaine, prilocaine)
• Mechanism: Block voltage-gated sodium channels in nerve membranes, preventing depolarization
• Work better in non-inflamed tissue (higher pH allows un-ionized form to penetrate)
• Metabolized in liver (amides) - use with caution in liver disease
• Vasoconstrictors (epinephrine, felypressin) added to:
  • Reduce systemic absorption of local anesthetic
  • Prolong duration of anesthesia
  • Reduce bleeding in surgical field

Drugs with Dry Mouth (Xerostomia) as Side Effect

• Anticholinergics (atropine, antihistamines)
• Antihypertensives (diuretics, beta-blockers)
• Antidepressants (tricyclics, SSRIs)
• Antipsychotics
• Opioid analgesics

Drug-Induced Gingival Enlargement

1. Phenytoin (anti-epileptic) - most classic
2. Cyclosporin (immunosuppressant)
3. Nifedipine and calcium channel blockers

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10. Prescription Writing

1. Superscription: Date, patient's name and address, Rx symbol
2. Inscription: Drug name, strength, and form
3. Subscription: Quantity to dispense
4. Signatura (Sig): Directions for patient
5. Prescriber's signature and DEA number (for controlled substances)

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11. Drug Nomenclature

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Summary: Key Concepts at a Glance

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