BIMM118!The Four Cornerstones of Pharmacokinetics!• Absorption!• Distribution!• Metabolism!• Elimination!Absorption and distribution are influenced by the formulation:!Medicinal Agent --> Formulation --> Medication!Galenic = Science of pharmaceutical formulation!Tinctures of natural products – opium, vegetable drugs!!!(Galenos of Pergamon, 129-199 AD) !2011!BIMM118!Drug Administration and Absorption!• Oral!!• Topical (Percutaneous)!• Rectal or Vaginal!• Pulmonal!• Parenteral!Routes of Drug Administration:!Route of administration determined by chemical properties and stability of the active substance, desired concentration needed at target tissue, sensitivity of the active agent to degradation (enzymatic) and desired duration of action.!BIMM118!Drug Uptake!Luellmann, 2011!Drug diffusion through phases: !• Aqueous phase – passive by concentration gradient*!!• Lipid phase – passive by both concentration gradient* & lipophilicity of drug!!Across barriers: !• Carriers!• Endocytosis / pinocytosis!!!Fickʼs Law:!Flux = [C1 – C2] X { P } X (Area)!!P is Permeability !!P = Permeability coefficient!! Thickness ! ! !!!BIMM118!Oral Drug Administration!• Pills!– Antiquated single-dose unit; round, produced by mixing !!drug powder with syrup and rolling into shape!!!!!!!!!• Tablets!– Oblong or disk-like shape, produced through mechanical pressure; filler !!material provides mass; starch or carbonates facilitate disintegration!!!BIMM118!Oral Drug Administration!• Coated Tablets!– Tablet covered by a “shell” (wax, highly specialized polymers = Eudragit®) to facilitate swallowing, cover bad taste or protect active ingredient from stomach acid!BIMM118!Oral Drug Administration!• Matrix Tablets!– Drug is embedded in inert “carrier” meshwork --> !!extended or targeted (intestinal) release!• Capsules!– Oblong casing (Gelatin); contains drug in liquid, !!powder or granulated form!!!!!• Troches or Lozenges; Sublingual Tablets!– Intended to be held in the mouth until dissolved!BIMM118!Oral Drug Administration!BIMM118!Oral Drug Administration!• Aequous Solutions (with Sugar=Syrup)!– Mostly for pediatric use!– 20 drops=1g!!!• Alcoholic Solutions (=Tinctures)!– Often plant extracts!– 40 drops=1g!!!• Suspensions!– Insoluble drug particles in aequous or lipophilic media!BIMM118!Percutaneous Drug Administration!Specific formulation determined by physician/dermatologist:! !• based on skin type:!– Dry vs. Oily!– Young vs. Old!– Intact vs. Injured!• based on drug properties:!– Hydrophilic vs. Lipophilic!– Soluble vs. Insoluble!BIMM118!Percutaneous Drug Administration!BIMM118!Percutaneous Drug Administration!• Ointment and Lipophilic Cream!– Either pure lipophilic base (lanolin=wool fat; paraffin oil; petrolium jelly) or !!“water-in-oil” emulsions!!• Paste!– Ointment with >10% pulverized solids (e.g. Zinc- or Titanium-Oxide)!• Lotion and Hydrophilic Cream!– “oil-in-water” emulsions!• Gels!– Either alcohol or aequous solution based (Ethanol gels --> Cooling effect)!– Increased consistency due to gel-forming agents!!BIMM118!Percutaneous Drug Administration!– Single Layer!• Inclusion of the drug directly within the skin-contacting adhesive. In this transdermal system design, the adhesive not only serves to affix the system to the skin, but also serves as the formulation foundation – Multi-Layer!• Similar to Single-layer, however, the multi-layer encompasses either the addition of a membrane between two distinct drug-in-adhesive layers or the addition of multiple drug-in-adhesive layers under a single backing film !– Reservoir!• Inclusion of a liquid compartment containing a drug solution or suspension separated from the release liner by a semi-permeable membrane and adhesive.!• Transdermal Drug Delivery Systems =“Patches”(Nicotin, Isosorbid-Nitrate, scopolamine)!BIMM118!Other Topical Drug Administration!• Eye Drops!• Sterile; Isotonic; pH-neutral!• Nose Drops/Nasal Sprays!• Viscous Solutions!• Pulmonary Formulations!• Inhalation anesthetics (Hospital use only)!• Nebulizers (mostly propellant operated) !• dispense defined amount of Aerosol ! (= dispersion of liquid or or solid particles in a gas)!• Size of aerosol particles determines depth of penetration into the respiratory tract:! !>100 µm: Nasopharynx!!10-100 µm: Trachea, bronchii!!<10 µm: Bronchioli, alveoli!!!!BIMM118!Other Topical Drug Administration!• Suppositories !• Drug incorporated into a fat with a melting point ~35ºC!• Rectal: Absorption mostly intended into systemic circulation (e.g. analgesics)!• Vaginal: Effects intended to be confined to site of application (e.g. candidiasis)!BIMM118!Parenteral Drug Administration!Sterile; iso-osmolar; pyrogen-free; pH=7.4!• Ampules!– Single use (mostly with fracture ring)!!• Single and Multi-dose Vials!– 10-100 ml; contain preservatives!• Cartridge ampules!!!!!• Infusions!– Solution administered over an extended period of time!BIMM118!Parenteral Drug Administration!• Advantages:!– 100% “Absorption”!– Drug enters general circulation without hepatic passage -->!! !No first-pass hepatic elimination!– Better bioavailability of hydrophilic drugs!!• Bioavailability/Speed of Absorption!– Intravenous (i.v.): !Fastest (infusions; cardio-vascular drugs)!– Intramuscular (i.m.): !Medium (anti-inflammatory; antibiotics)!– Subcutaneous (s.c.): !Slowest (vaccines; insulin; depot contraceptives)!!!BIMM118!Drug Distribution!BIMM118!Drug Distribution!• To be absorbed and distributed, drugs must cross barriers (membranes) to enter and leave the blood stream. !• Body contains two type of barriers which are made up of epithelial or endothelial cells:!– External (Absorption Barriers): Keratinized epithelium (skin), ciliated epithelium (lung), epithelium with microvilli (intestine), etc.!!These epithelial cells are connected via zonulae occludens (tight junctions) to create an unbroken phospholipid bilayer. Therefore, drugs MUST cross the lipophilic membrane to enter the body (except parenteral).!BIMM118!Drug Distribution!– Internal (Blood-Tissue Barriers): Drug permeation
View Full Document
Unlocking...