Four factors that influence drug membrane passage
Molecular Size - influenced by drug binding to plasma proteins; Lipid Solubility - generally a set characteristic of the drug, drugs usually hydrophobic and bind to plasma molecules to move about body, may be modified during metabolism leading to lower solubility; Degree of Ionization - less ionized better membrane passage, most drugs are weak acids or bases, metabolism may add sulfate group (pKa 1); Concentration Gradient - pretty straightforward.
When do you need to be concerned about a drug's bioavailability or plasma protein affinity?
Rarely. These are always calculated into the recommended dosage of the drug. Be aware if the effects of the drug change at a steady dose, however.
What are two very common drug metabolism pathways?
The body modifies the drug to be larger and less lipid soluble. This makes is much more difficult for the drug to move around and exert its effects.
What are three methods for drugs to diffuse across a membrane?
Passive diffuse through the membrane by lipid soluble drugs. Passive diffusion of small water soluble drugs through aqueous channels, ethanol and lithium enter this way. (Both rely on concentration gradients) Occasionally, the drug will closely resemble another substance which the cell actively transports and may enter via the transporter or via facilitated diffusion (not dependent on concentration gradient).
What are P-Glycoproteins?
P-Glycoproteins move drugs out of a cell across the cell membrane. Important in drug-drug interactions and antibiotic resistance.
What is unique about IV administration of a drug?
There is no absorption step.
What separates bioavailability from bioequivalence?
Bioavailability is a drug absorption parameter. Bioequivalence compares the bioavailbility of two different formulations.
What is amajor difference between oral administration of a drug and other (IV, IM, IO, etc.) administrations?
There are many things in the gut that may affect the bioavailability of a drug. This will primarily affect the rate that it is absorbed.
When is bioavailbility used?
To adjust the dosage when the route of administration is changed. A patient who takes a drug orally is in the hospital and the drug will be delivered IV, the absorption step is eliminated and 100% of the drug is delivered to the Cp, thus dosage must be recalculated. VERY RARELY done by physicians, adminstration route is calculated into dosages. New dose = old dose x old dose bioavailability.
What is important about the drug concentration in the plasma compartment?
Drug response is proportional to Cp concentration.
What is First Pass Metabolism?
There are drug metabolizing enzymes in the GI membranes and the liver that the drug must first pass before it arrives in the plasma. This has a significant effect on bioavailability.
What affects the bioavailability of drugs taken orally?
Survival of the drug in the digestive environment (aciditiy, digestive enzymes) The drug's ability to cross GI membranes - physiochemical properties (Small, uncharged, lipid soluble) Efficiency of drug metabolism - "First-Pass Effect" (wide drug and interpatient effect)
What routes are affected by first pass metabolism?
Oral and rectal routes. All other routes bypass this step, including sublingual (transmucosal) route. Sublingual nitro is given in 0.4mg doses, orally requires 40-120mg.
Why is rate of absorption not very important?
Because a prescription will be for the maintenance dose, and steady state will be acheived within 4-5 half lives. Rate of absorption is only important for the first dose.
How can rates of absorption be modified and why would they be?
Rates can be increased by using liquid preparations or rapidly dissovling tablets. Rates can be decreased with enteric coated products or sustained release preparations. This allows for longer release of drug into the system and greater time between peaks and troughs in the therapeutic window. Time to peak is slowed and Cpmax is blunted, but bioavailability is unaffected.
When are soluble formulations or insoluble formulations used?
Soluble formulations are used in IV or other rapid delivery routes and have immediate effects. IV = Inhalation > IM > SC > Oral Insoluble formulations are designed to slow the rate of absorption and extend the duration of action.
What defines the duration of a drug effect?
The time that the concentration is above the MEC (Minimum Effective Concentration)
What is bioequivalence considered to imply about therapeutic equivalence?
Bioequivalent products are considered to be therapeutic equivalents.
What factors are included to show bioequivalence of one formulation vs another?
The AUC and 90% CI across the study participants must lie within 80-125% of that of the brand drug.
What factors affect drug solubility?
The formulation must be hydrophilic to dissolve in an aqueous environment. The drug must be hydrophobic to cross membranes.
What influence does circulation and surface area at the site of adminstration have on drug absorption?
Higher circulation results in more rapid onset of effects. Diseases affecting circulation or exercise will affect absorption. Increased surface area will increase the rate of absorption (stomach vs intestine vs lung)
How do you maximize local effects over systemic effects with inhaled drugs?
Inhalation of PARTICLES will maximize local effects of the drug in the lungs, where the particles settle. Inhalation of volatile gases will favor systemic effects.
What is the difference between transdermal and dermal routes?
Transdermal refers to a route for a SYSTEMIC drug to enter the body (Think nicoteine patches). Dermal refers to a route for a LOCAL effect ON THE SKIN (cortisone creams).
What two categories of administration routes are there?
Enteral - Oral, Rectal
Parenteral - Sublingual, buccal, IV, IM, subcutaneous, Inhalation, transdermal
What administration routes allow for localization of drug effects?
Aural, Nasal, Throat, Vaginal, Ocular/Conjunctival, Inhalation (particles), Dermal (NOT transdermal)