M4

• Biopharmaceutics


  Combination of "Bio" meaning life and "Pharmaceutics" meaning the general area of study concerned with the formulation, manufacture, stability, and effectiveness of pharmaceutical dosage forms
• Biopharmaceutics


  • Examines the interrelationship of the physical/chemical properties of the drug, the dosage form in which the drug is given, and the route of administration on the rate and extent of systemic drug absorption
• Drugs are substances intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease
• Forms of drugs


  • Solids (tablets, capsules), semisolid, liquids, suspensions, emulsion, etc.
• Drug product


  Considered to be drug delivery systems that release and deliver the drug to the site of action, designed specifically to meet the patient’s needs including palatability, convenience, and safety
• Drug Product Performance


  The release of drug substance from the drug product for local drug action or for drug absorption into the plasma for systemic therapeutic activity
• Bioavailability


  Measurement of the rate and extent of active drug that reaches the systemic circulation, means access to the bloodstream
• Biopharmaceutical Consideration in Drug Product Design


  Involves factors that influence the design, stability, manufacture, release, dissolution, and delivery of the drug product
• Pharmacodynamics


  Relationship between the drug concentration at the site of action and pharmacologic response, including biochemical and physiologic effects that influence the interaction of drug with the receptor
• Toxicokinetic is the application of pharmacokinetic principles to the design, conduct, and interpretation of drug safety evaluation studies and in validating dose-related exposure in animals
• Clinical Toxicology is the study of adverse effects of drugs and toxic substances in the body
• Pharmacokinetics


  Science of the kinetics of drug absorption, distribution, metabolism, and excretion
• Principles of Pharmacodynamics


  Study of the biochemical and physiologic effects of drugs in biological systems, study of the mechanism by which these effects are produced
• Pharmacodynamics: Mechanism of Drug Action

  Receptor-mediated and Non-Receptor-mediated
• Pharmacodynamics


  Mechanism of Drug Action
• Receptor-mediated


  • Receptor – cellular macromolecule, or an assembly of macromolecules, that is concerned directly and specifically in chemical signaling between and within cells
• Non-Receptor-mediated


  • Examples: Direct chemical interaction – acid neutralizers (antacids), chelating agents (drugs that coat and bind to heavy metals that are present in excessive amount in the body), Colligative mechanism (dependent on the particles of the drug in solution)/ mass effect – osmotic diuretics, Counterfeit incorporation – purine-pyrimidine analogues
• Receptor Locations


  • Cell membrane
  • Cytoplasm
  • Nucleus
• Receptor Types


  • Cell membrane: GPCRs, Ion Channels, Kinases, Catalytic receptors, Enzymes, Transporters, Structural protein and other molecules, Cytoplasm and Nucleus: Structural protein and other molecules, Thyroid hormone receptor, Steroid receptors
• GPCR (G protein-coupled receptor)


  • 7-transmembrane spanning receptor, Metabotropic – effects due to metabolites (or 2nd messengers), Involved in signal transduction, Most common receptor
• Activation of Gs


  Activation of AC (Adenylyl cyclase), Increase in cAMP, Ex: Beta-receptors
• Activation of Gi


  Inhibition of AC (Adenylyl cyclase), Decrease in cAMP → inhibitory, Ex: alpha 2 presynaptic receptors
• Activation of Gq


  Activates PLC (Phospholipase C) – acts in triglycerides, Splits PIP2 → IP3 + DAG (2nd messengers; primarily involved in smooth muscles activities, so they increase intracellular calcium level in smooth muscles and are involved in the phosphorylation and activation of the myosin light chain kinase), Ex: alpha postsynaptic receptors, Location: smooth muscles → contraction
• Voltage-gated Ion channels


  Primarily governed by a change in the membrane potential, Prevents ions from moving in or out through the channel
• Gating mechanism in voltage-gated ion channels


  Prevents ions from moving in or out through the channel. A change in membrane potential leads to a change in gate configuration, allowing or preventing ion movement
• Voltage-gated Na+ channel


  • Blocked by Class I antiarrhythmics, local anesthetic, tetrodotoxin, saxitoxin
• Voltage-gated K+ channel


  • Blocked by Class III antiarrhythmics such as Amiodarone and Sotalol
• Voltage-gated Ca2+ channels


  • Blocked by CCBs such as Verapamil, Diltiazem, Amlodipine
• Ligand-gated channels


  Gating mechanism controlled by a binding site. Interaction with a ligand causes a change in gate configuration, allowing the movement of molecules or ions
• Nicotinic receptor (Na+) Channel

  • Blocked by neuromuscular blockers derived from tubocurarine
• GABAA receptors (Cl- channel)


  • Stimulated by BZDs, Barbs
• Kinases and Catalytic Receptors

  Receptors exist as monomers. Ligand interaction causes dimerization, leading to receptor activation
• Enzymes


  ACE converts Angiotensin I to Angiotensin II. COX is inhibited by NSAIDs. MAO is inhibited by MAO-Is. MAOA is inhibited by Moclobemide. MAOB is inhibited by Selegiline, Rasagiline, Safinamide
• Transporters


  Carrier molecules bring ions into or out of the cell by changing confirmation. Na+-K+ ATPase brings out 3 Sodium ions and brings in 2 Potassium ions, requiring energy or ATP
• Examples of Transporters


  • Na+-K+ ATPase: inhibited by Digitalis (Digoxin). Proton Pump (H+-K+ ATPase): inhibited by PPIs (Omeprazole)
• Structural Proteins and other molecules

  Microtubules consist of Dimers (α-tubulin and β tubulin) that can be added or removed from the chain, leading to polymerization or depolymerization
• Inhibitors of Microtubules


  • Griseofulvin, Colchicine, Anti-mitotics: Taxanes, Vincas, Estramustine, Epothilones (Ixabepilone)
• Depolymerization


  Shortening of the microtubule
• Microtubules


  • Cytoskeleton
  • Organelle movement
  • From mitotic spindles
• Inhibitors


  • Griseofulvin
  • Colchicine
  • Anti-mitotics - Taxanes, Vincas, Estramustine, Epothilones (Ixabepilone)