Comprehensive Study Notes on Basic Principles of Pharmacology and Pharmacokinetics

Fundamentals of Pharmacology and Pharmacodynamics

  • Pharmacology Definition: The study of drugs; specifically, articles used in the prevention, diagnosis, mitigation, treatment, and cure of diseases in humans and other animals.
  • Divisions of Pharmacology:
    • Pharmacodynamics: The study of the physiologic and biochemical effects of drugs in living systems and the mechanisms by which these effects are produced.
    • Pharmacokinetics: The study of what the body does to the drug, tracing the processes a drug undergoes as it reaches and leaves the site of action.
    • Pharmacotherapeutics: The study of the rational use of drugs in the management of diseases.
  • Types of Mechanisms of Drug Action:
    • Target Protein-Mediated Mechanisms: Involves a specific biologic site of action (referred to as the "action site" or "active site") where the drug targets a physiological protein.

Structural and Regulatory Protein Targets

  • Structural Proteins:
    • Microtubules: Made of alpha\text{alpha} and beta\text{beta} units of tubulin.
    • Microtubule Functions:
    • Keep organelles in place within eukaryotic cells.
    • Facilitate chemotaxis (cell movement mediated via a chemical stimulus).
    • Mediate the axonal release of neurotransmitters.
    • Facilitate mitosis and cell division (specifically during metaphase).
    • Drugs That Inhibit Microtubules:
    • Griseofulvin:
      • An antifungal drug used for the management of dermatomycosis (infection of the skin and appendages).
      • Mechanism: Arrests fungal mitosis.
      • Characteristics: Acts as an enzyme inducer; exhibits increased absorption when taken with fatty food.
    • Colchicine:
      • First-line treatment for acute gout and acute gouty attacks.
      • Mechanism: Inhibits the chemotaxis of immune cells that cause inflammation.
    • Antimitotics (Chemotherapy Drugs):
      • Taxanes: Paclitaxel, Docetaxel, Cabazitaxel.
      • Vinca Alkaloids: Vincristine, Vinblastine, Vinorelbine, Vindesine.
      • Estramastine.
  • Regulatory Proteins:
    • Function: Regulate cellular activity or function.
    • Voltage-Gated Channels:
    • Present in all cells to conduct changes in electrical signals.
    • Cellular Electrical States:
      • Resting/Polarized: Cells at rest carry a negative (−-) charge or are polarized.
      • Depolarization: Once excited, the cell becomes less negative or positive (++).
      • Repolarization: The cell returns to a negative (−-) charge to reach equilibrium.
      • Hyperpolarization: Renders the cell more negative (−-) and less excitable.
    • Dominant Electrolyte Distributions:
      • PISO: Potassium (K+K^+) Inside, Sodium (Na+Na^+) Outside.
      • MICO: Magnesium (Mg2+Mg^{2+}) Inside, Calcium (Ca2+Ca^{2+}) Outside.
      • PICHO: Phosphate (PO43−PO_4^{3-}) Inside, Chloride (Cl−Cl^-) Outside.
    • Physiological Importance of Key Ions:
      • Sodium (Na+Na^+) and Chloride (Cl−Cl^-): Maintain tonicity.
      • Calcium (Ca2+Ca^{2+}): Acts as a structural component in bones, mediates muscle contraction, and triggers the pre-synaptic release of neurotransmitters.
      • Magnesium (Mg2+Mg^{2+}) or MgSO4\text{MgSO}_4 (Epsom Salt): Functions as a natural calcium channel blocker (CCB). Competes with calcium at binding sites. Used in eclampsia (administered IV/IM as an anticonvulsant, or PO as a cathartic).

Ion Channel Blockers and Enzymatic Targets

  • Voltage-Gated Sodium Channel Inhibitors:
    • Class I Anti-arrhythmics:
    • Class IA: Disopyramide, Quinidine, Procainamide. Effect: Prolong the action potential (APAP).
    • Class IB: Tocainamide, Mexiletine, Lidocaine, Phenytoin. Effect: Shorten the action potential (APAP).
    • Class IC: Moricizine, Flecainide, Propanfenone, Encainide. Effect: No effect on the action potential (APAP).
  • Local Anesthetics:
    • Ester-Containing Local Anesthetics: Procaine, Cocaine. Characteristics: Short-acting.
    • Amide-Containing Local Anesthetics: Lidocaine, Bupivacaine. Characteristics: Long-acting.
    • Anti-convulsants with Na-Channel Activity: Phenytoin, Carbamazepine.
  • Voltage-Gated Potassium Channel Blockers:
    • Class III Antiarrhythmics: Amiodarone.
    • Insulin Secretagogues: Sulfonylureas (e.g., Glimeperide).
  • Calcium-Channel Blockers (CCB):
    • Dihydropyridines ("-dipines"): e.g., Nicardipine. Characteristics: Vasoselective (target arteries).
    • Non-DHP Class IV Antiarrhythmics:
    • Verapamil: Cardioselective treatment for arrhythmia.
    • Diltiazem: Intermediate effect on both the heart and blood vessels.
    • Contraindications: Contraindicated in patients with heart failure due to inefficient force of contraction of the heart.
  • Carrier Molecules:
    • Cell membrane proteins containing specific binding sites that undergo conformational changes to transport substances.
    • Na+/K+-ATPase\text{Na}^+/\text{K}^+\text{-ATPase} Pump:
    • Located in cardiac myocytes; responsible for calcium extrusion.
    • Activation of the NCX\text{NCX} (Sodium-Calcium Exchanger) is dependent on NKAP\text{NKAP} activation.
    • Inhibitors: Cardiac Glycosides, such as Digoxin (derived from Digitalis lanata, provides inotropic effects) and Digitoxin (derived from Digitalis purpurea).
    • H+/K+-ATPase\text{H}^+/\text{K}^+\text{-ATPase} Pump (Proton Pump):
    • Mediates the release of gastric acid.
    • Acetylcholine ($ ext{ACh}$), gastrin, and histamine binding at parietal cells trigger the release of hydrochloric acid ($ ext{HCl}$).
    • Inhibitors: Proton Pump Inhibitors (PPIs, ending in "-prazoles", e.g., Omeprazole). Most effective during state of hyperacidity.
  • Enzymatic Pathways and Inhibitors:
    • Eicosanoid Pathway:
    • Phospholipids serve as precursors for arachidonic acid, which yields prostaglandins and leukotrienes via cyclooxygenase ($ ext{COX}$) and lipoxygenase ($ ext{LOX}$) activities.
    • Prostaglandin: Functions in cytoprotection, pain, and inflammation. Derived from semen.
    • Leukotrienes: Cause bronchoconstriction.
    • Phospholipase A2 ($ ext{PLA2}$) Inhibitors: Corticosteroids (e.g., Prednisone).
    • 5-Lipoxygenase (5ext−LOX5 ext{-LOX}) Inhibitors: Zileuton (anti-asthma).
    • Cyclooxygenase ($ ext{COX}$):
    • Inhibited by Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as ASA (Aspirin), Ibuprofen, and Naproxen.
    • Angiotensin Converting Enzyme ($ ext{ACE}$):
    • Also known as "Kinase II" or "dipeptidyl decarboxypeptidase".
    • Inhibitors: ACE inhibitors (ending in "-prils").
    • Monoamine Oxidase ($ ext{MAO}$) Inhibitors:
    • MAO A: Metabolizes norepinephrine ($ ext{NE}$), epinephrine ($ ext{EPI}$), and serotonin (5ext−HT5 ext{-HT}). Deficiencies in serotonin and norepinephrine are linked to clinical depression.
    • MAO B: Metabolizes dopamine. Low levels of dopamine are linked to Parkinsonism.
    • Selective MAO A Inhibitor: Moclobemide.
    • Selective MAO B Inhibitors: Selegiline, Rosagiline.
    • Non-selective MAOIs: Phenelzine, Isocarboxazid, Tranylcypromine.
    • Atypical Antipsychotic Exception: Aripiprazole.
    • Catechol-O-methyltransferase ($ ext{COMT}$) Inhibitors:
    • Ending in "-capones": Tolcapone, Entacapone.

Receptor Classification and Signal Transduction

  • Receptors: Functional macromolecular cell components possessing a specific stereochemical configuration with which a ligand interacts, typically in a lock-and-key fashion.
    • Serotonin Blockers: Ending in "-setron" (e.g., Ondansetron), used for the management of cancer-induced nausea.
  • Type I: Ionotropic Receptors:
    • Associated directly with ligand-gated ion channels on the cell membrane.
    • Onset of action: Milliseconds ($ ext{ms}$).
    • GABAA\text{GABA}_A Receptor Complex:
    • Associated with Cl−\text{Cl}^- channels.
    • Stimulators: Benzodiazepines ($ ext{BZDs}$) and Barbiturates.
    • Barbiturates: Prolong the duration of Cl−\text{Cl}^- channel opening.
    • Benzodiazepines: Increase the frequency of Cl−\text{Cl}^- channel opening.
    • Mechanism: Enhances GABAA\text{GABA}_A receptor binding with GABA\text{GABA}, inducing an influx of Cl−\text{Cl}^- leading to hyperpolarization and central nervous system ($ ext{CNS}$) depression.
    • Nicotinic Receptors:
    • Associated with Na+\text{Na}^+ channels.
    • Subtypes: Nn\text{N}_n (neural/neuronal) and Nm\text{N}_m (neuromuscular / skeletal muscle).
    • Stimulators: Nicotine, Lobeline, Varenicline.
    • Inhibitors (Nm\text{N}_m blockers / skeletal muscle relaxants): Tubocurarine, Succinylcholine, Pancuronium, Atracurium ("-curium"), Rocuronium ("-curonium").
    • Glycine Blocker: Strychnine.
  • Type II: Metabotropic Receptors:
    • G-protein coupled receptors featuring 7-transmembrane spanning domains located on the cell membrane.
    • Onset of action: Seconds ($ ext{secs}$).
    • Operates by altering levels of secondary messengers.
    • Autonomic Nervous System ($ ext{ANS}$) G-Protein Distribution ("KISS KICK"):
    • Gq\text{G}_q: alpha1\text{alpha}_1, M1\text{M}_1, M3\text{M}_3, Histamine-1, Vasopressin-1, post-synaptic alpha2\text{alpha}_2
    • Gi\text{G}_i: alpha2\text{alpha}_2 (pre-synaptic), M2\text{M}_2, Dopa-2
    • Gs\text{G}_s: beta1\text{beta}_1, beta2\text{beta}_2, H2\text{H}_2, V2\text{V}_2, Dopa-2
    • Secondary Messengers:
    • Cyclic adenosine monophosphate ($ ext{cAMP}$)
    • Cyclic guanosine monophosphate ($ ext{cGMP}$) — utilizes identical signaling cascades in intestinal mucosa and blood vessels
    • Inositol triphosphate ($ ext{IP}_3$)
    • Diacylglycerol ($ ext{DAG}$)
    • Specific G-Protein Functions:
    • Gs\text{G}_s: Stimulates adenylyl cyclase ($ ext{AC}$). Includes beta\text{beta}-receptors. Stimulated by Epinephrine and Norepinephrine; blocked by beta\text{beta}-blockers ("-olols").
    • Gi\text{G}_i: Inhibits adenylyl cyclase ($ ext{AC}$), decreasing cAMP\text{cAMP}. Examples include pre-synaptic alpha2\text{alpha}_2 receptors (stimulated by Clonidine, Methyldopa, Guanfacine, Guanabenz) and M2\text{M}_2 receptors.
    • Gq\text{G}_q: Stimulates Phospholipase C ($ ext{PLC}$), which catalyzes the formation of IP3\text{IP}_3 and DAG\text{DAG} from PIP2\text{PIP}_2. Increases intracellular calcium ions (Ca2+\text{Ca}^{2+}), causing smooth muscle contraction. Examples include alpha1\text{alpha}_1 (blocked by "-zosin" drugs like Alprazosin), M1\text{M}_1, and M3\text{M}_3 receptors.
  • Type III: Enzyme-Linked Receptors:
    • Membrane-bound receptors; onset of action takes minutes.
    • Example: Insulin receptor (tyrosine kinase-linked).
    • Effects: Stimulates glucokinase (promoting glycolysis) and induces translocation of glucose transporters (GLUT2\text{GLUT2}, GLUT4\text{GLUT4}) into the cell membrane.
    • Other Examples: Platelet-derived Growth Factor, Epidermal Growth Factor.
  • Type IV: Gene Transcription-Linked / Nuclear / Intracellular Receptors:
    • Located inside the cell (cytoplasm or nucleus); onset takes hours.
    • Directly modulates gene transcription ($ ext{DNA}$ to RNA\text{RNA}).
    • Ligands/Drugs: Sex hormones, thyroid hormones, Vitamin D, steroidal hormones (corticosteroids).

Non-Target Protein Mechanisms and Receptor Interactions

  • Non-Target Protein Mediated Mechanisms:
    • Colligative Mechanism / Mass Effect:
    • Dependent on physical colligative properties and solute particle concentrations (e.g., vapor pressure lowering, boiling point elevation, freezing point depression, osmotic pressure).
    • Mannitol: Acts as an osmotic diuretic/aquaretic. Given via IV infusion, it inhibits water reabsorption in water-permeable regions of renal tubules (descending limb of loop of Henle) by increasing osmotic pressure. Given orally (PO), it causes osmotic diarrhea.
    • Chemical Antagonism / Direct Chemical Interaction:
    • Local Antacids: Neutralization reaction using Mg(OH)2\text{Mg(OH)}_2 or Al(OH)3\text{Al(OH)}_3
    • Systemic Antacids: Neutralization using NaHCO3\text{NaHCO}_3 for metabolic acidosis.
    • Protamine Sulfate: Neutralization reaction for heparin (acidic) toxicity, yielding ionized heparin (ionized drugs are excreted rather than absorbed).
    • Chelating Agents: British Anti-Lewisite ($ ext{BAL}$) or dimercaprol (IM in peanut oil vehicle) for Mercury ($ ext{Hg}$) and Arsenic ($ ext{As}$) toxicity; Penicillamine ($ ext{Cuprimine}$) for Copper ($ ext{Cu}$) toxicity in Wilson's disease; Deferoxamine ($ ext{Desferal}$) for Iron ($ ext{Fe}$) toxicity.
    • Counterfeit or Incorporation Mechanism:
    • Uses purine and pyrimidine base analogues (antimetabolites used as anti-cancer agents), e.g., 5-fluorouracil.
  • Drug-Receptor Binding Characteristics:
    • Affinity: The capacity of a drug to bind to a specific receptor.
    • Intrinsic Activity (IAIA): The ability of a bound ligand to evoke a functional biological response (constitutive activity).
  • Ligand Classifications:
    • Agonist: Possesses affinity and positive intrinsic activity (IA>0IA > 0).
    • Antagonist: Possesses affinity but zero intrinsic activity (IA=0IA = 0).
    • Inverse Agonist: Produces an effect opposite to the agonist, decreasing intrinsic activity (IA<0IA < 0).

Dose Response Curves for Agonist, Antagonist, and Inverse Agonist

  • Types of Agonists:
    • Full Agonist: Produces the maximum achievable biological effect (IA=1IA = 1), e.g., Morphine at mu\text{mu} receptors.
    • Partial Agonist: Produces submaximal responses (0<IA<10 < IA < 1) and exhibits mixed agonist-antagonist characteristics. In the presence of a full agonist, a partial agonist acts as a competitive antagonist.
    • Nalbuphine: Acts as a partial agonist/antagonist; reduces morphine-induced analgesia when co-administered.
    • Tamoxifen: Partial agonist at estrogen receptors used in breast cancer management.
  • Types of Antagonists:
    • Functional / Physiologic Antagonism: Two ligands bind to different receptor types to produce opposing physiological effects.
    • Example: Epinephrine in anaphylaxis. Anaphylaxis releases histamine (binding H1\text{H}_1 to cause bronchoconstriction and vasodilation/hypotension). Epinephrine binds alpha1\text{alpha}_1 (causing vasoconstriction) and beta2\text{beta}_2 (causing bronchodilation) to reverse shock.
    • Pharmacologic / Receptor Antagonism: Binding of an antagonist to the same receptor as the agonist, blocking its response (e.g., Diphenhydramine blocking Histamine at H1\text{H}_1 receptors; beta\text{beta}-blockers inhibiting Epinephrine).
    • Chemical Antagonism: Direct chemical interaction between two substances, neutralizing the target (e.g., Protamine sulfate neutralizing acidic Heparin).
  • Reversibility and Surmountability:
    • Reversible Antagonism: Temporary interaction (<24 hours<24\text{ hours}) sustained by weak non-covalent interactions (van der Waals forces, hydrogen bonds).
    • Irreversible Antagonism: Permanent inhibition (lasting days to weeks) maintained by strong covalent bonds until new receptors are synthesized.
    • Competitive / Surmountable: Antagonism can be fully overcome by increasing the concentration of the agonist.
    • Non-competitive / Non-surmountable: Cannot be overcome by adding more agonist; typically occurs at an allosteric site (a site distinct from the agonist binding site).
  • Historical Theories of Drug Action:
    • Hypothesis of Clark: Biological effect is directly proportional to the fraction of receptors occupied; full effect occurs when all receptors are occupied.
    • Hypothesis of Paton (Rate Theory): Pharmacological response depends on the rate of drug-receptor associations per unit time (stimulus).
    • Hypothesis of Ariëns and Stephenson: Effects persist as long as drug-receptor complexes remain occupied.

Dose-Response Graphs and Pharmacokinetic Principles

  • Graded Dose-Response Relationship:
    • Plot: Degree of Response versus Dose or Log Dose. Plotting against Dose yields a hyperbolic curve; plotting against Log Dose yields a sigmoidal curve.
    • Parameters:
    • Efficacy (Ceiling Effect): The maximum achievable pharmacological response.
    • Potency: The dose required to produce 50%50\% of the drug's maximum efficacy.
    • Slope: The degree of change in response relative to changes in dose. A steep slope requires a "start low, go slow" dosing approach due to drastic response shifts; a shallow slope allows safer dose adjustments.
    • Ceiling Dose: The smallest dose required to yield the maximum achievable response.
    • Antagonist Shifts:
    • Competitive Antagonists: Shift the log dose-response curve to the right without altering maximum efficacy.
    • Non-competitive Antagonists: Depress the maximum response height, failing to reach full efficacy despite higher agonist doses.
  • Quantal Dose-Response Relationship:
    • Plot: Cumulative percentage of population responding versus Log Dose (all-or-none response).
    • Parameters:
    • Median Effective Dose (ED50ED_{50}): The dose producing a specified therapeutic effect in 50%50\% of the population.
    • Median Toxic Dose (TD50TD_{50}): The dose producing a specific toxic response in 50%50\% of the population.
    • Median Lethal Dose (LD50LD_{50}): The dose causing mortality in 50%50\% of animal study populations during pre-clinical trials.
    • Therapeutic Index (TITI): A relative measure of drug safety calculated as:       TI=TD50ED50TI = \frac{TD_{50}}{ED_{50}}       Higher TITI values indicate a safer drug profile.
    • Margin of Safety: Represents the margin between therapeutic and toxic doses.

Quantal Dose Response Graph

  • Pharmacokinetics Overview (LADME):
    • Processes Involved: Liberation, Absorption, Distribution, Metabolism, Excretion.
    • Biopharmaceutics: The study of how dosage forms, routes of administration (PO, IV, IM), and physicochemical properties (pKapK_a, pHpH) impact bioavailability.

Drug Transport Mechanisms

  • General Requirements: Drugs must exist in aqueous solution to cross cell membranes, except during pinocytosis (where drugs are in micelle form: oil globules stabilized by surfactants).
  • Passive Diffusion:
    • Most common and dominant transport pathway; slowest rate; requires no metabolic energy (ATP\text{ATP}).
    • Drives transport down a concentration gradient (high to low concentration).
    • Governed by Fick's Law of Diffusion:     dQdt=D×A×kh(CGI−Cp)\frac{dQ}{dt} = \frac{D \times A \times k}{h} (C_{GI} - C_p)
    • dQdt\frac{dQ}{dt} = Rate of diffusion
    • CGI−CpC_{GI} - C_p = Concentration gradient between gastrointestinal lumen and plasma
    • DD = Diffusion coefficient
    • AA = Surface area of the membrane
    • hh = Membrane thickness
    • kk = Partition coefficient
    • Factors Influencing Passive Diffusion:
    • Concentration Gradient, Surface Area, and Diffusion Coefficient: Directly proportional to diffusion rate.
    • Membrane Thickness: Inversely proportional to diffusion rate.
    • Particle Size: Inversely related to diffusion coefficient.
    • Lipophilicity: Directly proportional to diffusion coefficient.
    • Ionization State:
      • Unionized Form (HAHA): Lipophilic, non-polar, readily absorbed ("LUNA": Lipophilic Unionized Non-polar Absorbed).
      • Ionized Form (H++A−H^+ + A^-): Hydrophilic, polar, preferentially excreted ("HIPE": Hydrophilic Ionized Polar Excreted).
      • Acid dissociation constant (kAk_A) and negative log (pKa=−log⁡(kA)pK_a = -\log(k_A)). Higher pKapK_a values favor non-ionized states for weak bases and diffusion.
    • Partition Coefficient (KK):       K=CoilCwaterK = \frac{C_{\text{oil}}}{C_{\text{water}}}       Higher KK values indicate greater lipophilicity and faster diffusion.
  • Carrier-Mediated Transport:
    • Features selectivity and specificity (e.g., Levodopa utilizes the Large Neutral Amino Acid Transporter, LNAAT\text{LNAAT}, to cross the blood-brain barrier).
    • Subject to competitive inhibition (e.g., Levodopa should be taken before meals to prevent competition with dietary amino acids).
    • Saturable due to fixed carrier capacity; demonstrates Michaelis-Menten (non-linear, capacity-limited) kinetics.
    • Kinetics Orders:
    • First-Order Kinetics: Rate of elimination is directly dependent on drug concentration.
    • Zero-Order Kinetics: Rate of clearance is constant and independent of drug concentration.
    • Types of Carrier Transport:
    • Active Transport: Requires energy (ATP\text{ATP}); moves drugs against concentration gradients (uphill); fastest mechanism.
    • Facilitated Diffusion: Requires a carrier protein but no energy; moves along concentration gradients.
  • Convective Transport / Bulk Flow:
    • Movement of drugs through water-filled membrane pores (paracellular transport).
    • Characteristics: Pore size 7–10 A˚7\text{--}10\,\text{\AA}, transports molecules with molecular weights <150–400 Da<150\text{--}400\,\text{Da}. Charged pore linings permit opposite-charge ion passage via solvent drag down concentration gradients.
  • Ion-Pair Transport:
    • Enables transport of large charged ionic species (e.g., tertiary NH4+\text{NH}_4^+ neutralizing negatively charged mucin).
    • Forms an uncharged neutral complex via direct interaction prior to passive diffusion.
  • Pinocytosis / Phagocytosis:
    • Vesicle-mediated, energy-requiring bulk transport.
    • Basic requirement: Drugs must be formulated into micelles (oil globules stabilized by surfactants like liver-produced bile, whose secretion is triggered by pancreatic cholecystokinin upon fatty food intake).
    • Examples: Griseofulvin, fat-soluble vitamins (A, D, E, K).

Liberation, Absorption, and Bioavailability

  • Liberation:
    • Release of the active pharmaceutical ingredient ($ ext{API}$) from its dosage form to produce an aqueous solution.
    • Highly modifiable process (e.g., controlled-release delivery systems). True solutions bypass liberation (absorption is rate-limiting).
    • Pharmacotechnical Factors: Formulation, quality, disintegration rate, dissolution rate.
  • Absorption:
    • Physiologic Absorption: Rate and extent of drug disappearance from the administration site.
    • Pharmacokinetic Absorption: Rate and extent of drug entry into systemic circulation.
  • Bioavailability (BABA or FF):
    • Measure of the rate and extent of active drug entry into systemic circulation.
    • Determined via: Cumulative Urinary Excretion Data or Plasma Concentration vs Time Graphs.
    • Key Pharmacokinetic Parameters:
    • Cmax⁡C_{\max}: Maximum achieved plasma concentration; measures both rate and extent of absorption; highly variable.
    • Tmax⁡T_{\max}: Time required to reach Cmax⁡C_{\max}; measures absorption rate only.
    • AUCAUC (Area Under Curve): Total integrated drug exposure over time; measures extent of absorption (most critical parameter).
    • Calculations for Bioavailability (FF):
    • Absolute Bioavailability (FabsF_{\text{abs}}): Compares non-IV administration to IV administration at identical doses:       Fabs=AUCnon-IVAUCIVF_{\text{abs}} = \frac{AUC_{\text{non-IV}}}{AUC_{\text{IV}}}
    • Relative Bioavailability (FrelF_{\text{rel}}): Compares generic formulations to an innovator reference standard given at equal doses via the same route:       Frel=AUCgenericAUCreferenceF_{\text{rel}} = \frac{AUC_{\text{generic}}}{AUC_{\text{reference}}}
  • Factors Influencing Absorption:
    • Dose Size: Directly increases absorption rate and extent.
    • Environmental pH:
    • Weak acids (e.g., Aspirin [ASA\text{ASA}]) are unionized and absorbed in acidic stomach environments, but ionized and excreted in alkaline intestinal environments.
    • Weak bases are ionized and excreted in the stomach, but unionized and absorbed in the small intestine.
    • Surface Area: Small Intestine (120 m2120\,\text{m}^2 due to villi and microvilli) >> Stomach; Lungs >> Small Intestine >> Stomach.
    • Perfusion Degree: Small intestine receives higher blood flow than the stomach. Co-administering epinephrine with local anesthetics reduces local blood flow, minimizing systemic absorption, toxicity, and surgical bleeding while prolonging anesthetic duration.
    • Gastric Emptying Time (GET\text{GET}):
    • Time required for stomach contents to empty into the small intestine (normally 2–3 hours2\text{--}3\text{ hours}).
    • Accelerated emptying (lower GET\text{GET}) speeds up absorption.
    • Factors Increasing GET\text{GET} (Slowing Absorption): High fat or protein meals, heavy meals, stress, strenuous heavy exercise, gastric ulcers, lying on the left side, anticholinergics, opioids, morphine, nalbuphine.
    • Factors Decreasing GET\text{GET} (Accelerating Absorption): Extreme food temperatures, light exercise, diabetes mellitus, lying on the right side, cholinomimetics, prokinetic agents (domperidone, metoclopramide).
  • Product Classifications and Equivalency:
    • Bioequivalence: Similarity in BABA (AUCAUC, Cmax⁡C_{\max}, Tmax⁡T_{\max} ratios) between a generic drug and an innovator standard.
    • Pharmaceutical Equivalents: Drug products containing identical active ingredients (API\text{API}), salt/ester forms, dosage forms, and strengths, though excipients (colorants, flavorants) may differ.
    • Pharmaceutical Alternatives: Products sharing the same API\text{API} that differ in salt/ester form (e.g., Diclofenac Sodium vs. Diclofenac Potassium), strength, or dosage form.
    • Therapeutic Equivalents: Pharmaceutical equivalents that demonstrate bioequivalence.
    • Therapeutic Alternatives: Distinct API\text{API} molecules belonging to the same pharmacological class (e.g., Ibuprofen vs. Naproxen).

Distribution and Plasma Protein Binding

  • Distribution:
    • Reversible movement of drug molecules between systemic circulation, tissues, and extracellular fluid spaces.
    • Influencing Factors:
    • Cardiac Output (CO\text{CO}): Blood volume pumped per minute (normal range: 2.2–3.5 L/min/m22.2\text{--}3.5\,\text{L/min/m}^2). Higher CO\text{CO} enhances systemic distribution.
    • Regional Blood Flow: Direct proportion of cardiac output supplied to specific organ systems:
      • Lungs: 100%100\%
      • Liver: 25%25\%
      • Kidneys: 25%25\%
      • Bone and Adipose Tissue: <1%<1\%
      • Clinical Implication: High perfusion allows lung infections to resolve in 7–10 days7\text{--}10\text{ days}, whereas low perfusion in bone tissue requires long-term antimicrobial therapy (at least 6 weeks6\text{ weeks}).
  • Volume of Distribution (VdV_d):
    • Hypothetical volume of fluid needed to contain the total amount of drug in the body at a concentration equal to that in plasma (expressed in Liters):     Vd=AbCpV_d = \frac{A_b}{C_p}     Where AbA_b is the total dose/amount of drug in the body, and CpC_p is plasma drug concentration.
    • Clinical Utility: Used to estimate loading doses and determine the extent of drug tissue binding versus vascular confinement.
  • Plasma Protein Binding:
    • Binding Selectivity:
    • Albumin: Preferentially binds weak acidic drugs.
    • Alpha1\text{Alpha}_1 -Acid Glycoprotein: Preferentially binds weak basic drugs.
    • Globulins: Bind endogenous hormones.
    • Consequences: Bound drug fractions are pharmacologically inactive, restricted from entering tissue compartments, and protected from clearance, prolonging duration of action. Highly bound drugs (e.g., Warfarin, Phenylbutazone, Midazolam, Sulfa drugs) are vulnerable to displacement interactions, potentially causing adverse drug reactions (ADRs\text{ADRs}).

Drug Metabolism (Biotransformation)

  • Biotransformation Objectives: Conversion of lipophilic drugs into inactive/less active, non-toxic, polar, water-soluble metabolites suitable for renal excretion.
  • Metabolic Exceptions:
    • Prodrug Activation: Inactive precursor converted to active drug (e.g., conversion of Enalapril to Enalaprilat; Clopidogrel; Dipivefrin). Note: All ACE inhibitors are prodrugs except Captopril, Lisinopril, and Enalaprilat (which are active drugs used in acute states).
    • Toxic Metabolite Formation: Oxidation of Acetaminophen ($ ext{APAP}$) yields the hepatotoxic metabolite NN-acetyl-pp-benzoquinone imine ($ ext{NAPQI}$).
    • Active to Active Conversion: Transformation of an active parent compound to an active metabolite (e.g., Diazepam to Oxazepam).
  • Organs of Biotransformation: Liver (primary/dominant organ), Kidneys, Gastrointestinal Tract ($ ext{GIT}$), Placenta, Plasma.
  • First-Pass Effect (Pre-Systemic Metabolism):
    • Metabolism of orally administered drugs during initial passage through gut mucosa and liver before reaching systemic circulation, drastically reducing oral bioavailability.
    • Drugs exhibiting high first-pass clearance: Propranolol, natural opiates, synthetic opioids, catecholamines (Epinephrine, Norepinephrine, Dopamine), Felodipine, Lidocaine.
  • Phase I Metabolism (Functionalization / Asynthetic Phase):
    • Unmasks or adds polar functional groups (−OH-\text{OH}, −NH2-\text{NH}_2, −SH-\text{SH}) to increase hydrophilicity.
    • Oxidation Reactions (Dominant Pathway):
    • Cytochrome P450 Enzymes (CYP450):
      • CYP1A2: Acetaminophen ($ ext{APAP}$), Theophylline, Caffeine.
      • CYP2C9: S-Warfarin, Phenytoin.
      • CYP2C19: Proton Pump Inhibitors ($ ext{PPIs}$), Clopidogrel, Propranolol.
      • CYP2D6: Codeine, Tamoxifen, selective antipsychotics, antidepressants, beta\text{beta}-blockers.
      • CYP3A4, CYP3A5, CYP3A7: Azole antifungals, Calcium Channel Blockers ($ ext{CCBs}$), macrolides, HIV antivirals, tyrosine kinase inhibitors.
    • Non-CYP Mediated Oxidation: Catalyzed by Monoamine Oxidase ($ ext{MAO}$) and Aldehyde Dehydrogenase.
    • Reduction Reactions: Addition of hydrogen or removal of oxygen.
    • Nitroreduction (e.g., Chloramphenicol)
    • Carbonyl reduction (e.g., Naloxone, Methadone)
    • Azo reduction (e.g., Prontosil)
    • Hydrolysis Reactions:
    • Ester cleavage: Ester local anesthetics, ACE\text{ACE} inhibitors, Aspirin (ASA\text{ASA}).
    • Amide cleavage: Lidocaine, Procainamide.
    • Thyroid Hormone Note: Propranolol (beta\text{beta}-blocker) inhibits peripheral conversion of T4T_4 to T3T_3.
  • Phase II Metabolism (Conjugation / Synthetic Phase):
    • Attachment of endogenous polar groups to parent drugs or Phase I metabolites.
    • Glucuronidation: Dominant Phase II pathway in adults, catalyzed by Uridine-5'-diphosphoglucuronosyl transferase (or glucuronosyl acyl transferase). Underdeveloped in neonates (who rely primarily on sulfation).
    • Acetylation: Catalyzed by NN-acetyltransferase ($ ext{NAT2}$). Substrates include Hydralazine, Isoniazid ($ ext{INH}$), and Procainamide.
    • Other Conjugation Pathways:
    • Glycine Conjugation: Conjugates carboxylic acid, salicylic acid, and benzoic acid.
    • Methylation: Mediated by Catechol-OO-methyltransferase ($ ext{COMT}$) for catecholamines.
    • Sulfation: Conjugates Paracetamol.
    • Glutathione Conjugation: Neutralizes reactive electrophilic free radicals.
    • Glutamate Conjugation.
  • Enzyme Induction and Inhibition:
    • Enzyme Induction: Stimulates metabolic activity. Increases clearance of active drugs (lowering efficacy), enhances prodrug activation (increasing efficacy/toxicity), or elevates toxic metabolite production.
    • Enzyme Inhibition: Decreases metabolic enzyme activity. Impairs active drug clearance (increasing toxicity) or impairs prodrug conversion (reducing efficacy).

Drug Excretion and Pharmacogenetics

  • Excretion:
    • Permanent loss of unchanged drug or metabolites from the body; requires compounds to be polar and water-soluble.
  • Renal Excretion Pathways:
    • Main excretory organ; requires low molecular weight compounds (<400–600 Da<400\text{--}600\,\text{Da}).
    • Glomerular Filtration: Passive process filtering unbound drug fractions. Estimated by Creatinine Clearance (CrClCrCl) via the Cockcroft-Gault Equation:     CrCl=(140−Age)×BWSerumCr×72CrCl = \frac{(140 - \text{Age}) \times \text{BW}}{\text{SerumCr} \times 72}(Where Age is in years, Body Weight [\text{BW}] is in kg, and Serum Creatinine is in mg/dL. For female patients, multiply the calculated value by 0.850.85 to obtain clearance in mL/min\text{mL/min}).
    • Tubular Secretion: Active, carrier-mediated transport from peritubular capillaries into the renal tubular lumen.
  • Biliary Excretion and Enterohepatic Recycling:
    • Excretion of high molecular weight polar compounds into bile and stool.
    • Enterohepatic Circulation: Drugs excreted in bile enter the small intestine, where gut flora may deconjugate metabolites back into non-polar forms, enabling intestinal reabsorption back to the liver. This recycling prolongs drug retention and increases toxicity risks.
  • Miscellaneous Excretion Routes:
    • Lungs: Excretion of non-polar volatile compounds (e.g., gaseous anesthetics).
    • Sweat Glands: Elimination via sweat.
    • Mammary Glands: Excretion into breast milk.
  • Pharmacogenetics and Genetic Polymorphisms:
    • Genetic variations in drug-metabolizing enzyme expression levels:
    • CYP2D6 Variations:
      • Extensive Metabolizers (EM\text{EM}): Normal enzymatic activity.
      • Poor Metabolizers (PM\text{PM}): Reduced or absent enzymatic activity.
      • Ultra Metabolizers (UM\text{UM}): Markedly increased enzymatic activity.
    • NN-Acetyltransferase 2 ($ ext{NAT2}$) Polymorphisms:
      • Slow Acetylators: Predominant in Caucasian populations (PM\text{PM} phenotype).
      • Fast Acetylators: Predominant in Asian populations (EM\text{EM} phenotype).