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Module 2: PPT 2- pharmacokinetics
The process of drug absorption applies to all routes of administration, except for which routes? - the topical route: where drugs are applied directly on the target tissue, and the intravenous route where the drug is already in the circulation. Drug absorption is determined by what factors? - •Dosage form •Dissolution time (Rate) •Route of administration •Size of drug molecule •Drug concentration •Perfusion •pH •Cell membrane properties •Food/drug interactions •Adherence Regardless of the route of administration, drugs must be in what? Give an example of this. - in solution to be absorbed Thus, solid forms (eg, tablets) must be able to disintegrate and de-aggregate before the drug can be absorbed. drugs face a greater barrier to absorption after what type of administration? - drugs face a greater barrier to absorption after oral administration than from parenteral Drugs injected into the subcutaneous tissue and muscle bypass what? -
parenteral: the epithelial barrier and are more easily absorbed through spaces between capillary endothelial cells. In the gut, lungs, and skin, drugs must first be absorbed through what? - oral: a layer of epithelial cells that have tight junctions. What is dissolution? - the transformation of a solid substance (such as a tablet) into a solution. What does increased solubility and increased viscosity do to dissolution? - •Increased solubility increases rate of dissolution •Increased viscosity decreases the rate of dissolution The rate of dissolution is a key target for? - controlling the duration of a drug's effect; and as such, several dosage forms that contain the same active ingredient may have been developed, differing only in the rate of dissolution. If a drug is supplied in a form that is not readily dissolved what will occur? - the drug may be released more gradually over time with a longer duration of action. Having a longer duration of action may improve patient adherence since the medication will not have to be taken as often. slow-release dosage forms will do what to drug concentrations versus quick release forms? - slow-release dosage forms may maintain concentrations within an acceptable therapeutic range over a long period of time, as opposed to quick-release dosage forms which may result in sharper peaks and troughs in serum concentrations. The outer part of a lipid bilayer is? - hydrophilic the middle part of the matrix is? -
What does this other type of absorption require? - active transport or by facilitated diffusion it requires a carrier molecule and a form of energy provided by ATP because it can transfer drugs across a concentration gradient To diffuse across the intestinal wall, a molecule must be less than what and most molecules that diffuse easily are? - less than 1000 daltons in diameter 250-600 daltons Why is size important when explaining to your patients why some drugs cannot be given orally? - unfractionated heparin and insulin—substances whose molecular size is about 50,000 daltons and 5,500 daltons What do acids do? What do bases do? - •Acids donate protons (+ charged ions): an acid is a substance that releases positively charged hydrogen ions (H+) when it is in solution •Bases accept protons: A base is a substance that can bind H+ ions by accepting the protons, attaching them to a compound, and then removing them from solution. That is why if you add a base to an acid solution, it will make it less acidic When strong acids, strong bases, and strong electrolytes are dissolved in a solution what occurs? - these substances will nearly completely dissociate into their hydrogen or hydroxyl ions, and this dissociation is called ionization. What happens when weak acids and bases try to ionize? -
they are only partially ionized in aqueous solution and therefore yield a mixture of the un- dissociated compound and the ions Drugs that are non-ionized at normal plasma pH (i.e. 7.4) have what polarity and lipid solubility? - low polarity, and highly lipid-soluble cross cell membranes easily Drugs that are ionized at normal plasma pH have what polarity and lipid solubility? - high-polarity, and lower lipid solubility do not cross cell membranes easily The ratio of the ionized and non-ionized forms at a particular target site influences what? - the rate of absorption and is also a factor in distribution and elimination What does polarity refer to? - how ionized a substance is Drugs that have low polarity when in solution cross what? - lipid membranes more easily. A highly polar substance is one that? - is highly ionized or dissociated in a solution. Drugs that are highly polar in solution do not cross the lipid cell membrane easily. Many drugs are what time of acid and base? - weak acids or bases that exist as a mixture of both ionized (which means that the drug has an electrical charge when dissolved in body fluids) and non-ionized (uncharged) forms in the body The site of absorption determines which factors? - gastric emptying time or gastric volume and intestinal motility, will also have an effect on a specific drug's absorption
Following the oral administration of drugs, the plasma concentration generally reaches, in principle, a single, well-defined peak (Cmax) when? - at the time of Tmax Before Cmax is reached, on the upslope of the curve shown here, absorption is? - higher than elimination; and after Cmax is reached, the situation is reversed distribution is the? - reversible transfer of drugs from one body compartment (the vascular space) to another (the extravascular space) via the systemic circulation distribution is what kind of process? what is the driving force? - a passive process; the driving force is the concentration gradient between the vascular and extravascular compartments. The process occurs by diffusion of free, unbound drug between the two compartments until equilibrium is achieved distribution plays a significant part in? - the onset, intensity, and duration of the drug's effect How are most drugs distributed? - Most drugs are not uniformly distributed throughout total body water, and some drugs are restricted to either the extracellular fluid or plasma compartment. What is the one compartment model? - The one-compartment model illustrated in this slide assumes that once a drug enters the body, it is rapidly distributed evenly throughout all body tissues and then eliminated from the body. Ex: the aminoglycosides such as gentamycin. This drug is completely distributed 15-30 minutes after administration.
However, not all drugs rapidly reach equilibrium throughout the body; some are absorbed more slowly and/or are preferentially distributed to certain tissues. What is the two compartment model? - In the two-compartment model, the drug is absorbed into the central compartment (the blood) and then distributed to the peripheral compartment (the tissues). The drug then equilibrates between the central and peripheral compartments and is eventually excreted from the body via the systemic circulation. An example of this type of drug is vancomycin whose distribution phase is 1-2 hours. The rate at which a drug is distributed to various organs after a drug dose is administered depends largely? - on the proportion of cardiac output received by the organs Drugs are rapidly distributed to highly perfused tissues, which are? Drugs are distributed more slowly to less perfused tissues such as? - namely the brain, heart, liver, and kidney; and this enables a rapid onset of action of drugs affecting these tissues skeletal muscle and even more slowly to those with the lowest blood flow, such as skin, bone, and adipose tissue what is the extent of plasma protein binding? - only unbound drugs are bioactive Almost all drugs are reversibly bound to plasma proteins, primarily? - albumin Lipid solubility is a major factor affecting the extent of drug distribution, particularly to? - the brain, where the bloodbrainbarrier restricts the penetration of polar and ionized molecules
What is the bioavailability variable noted by? What is the value? How is it assessed? - •Variable is noted by the letter "F" (for "fraction") •Value is a percent between 0 and 1 •Assessed by determining area under plasma concentration-time curve (AUC) compared to AUC for IV drug (100% bioavailable) AUC is directly proportional to? - the total amount of unchanged drug that reaches systemic circulation What are the factors influencing bioavailability? - •Route of administration •Disintegration/dissolution of drug •First-pass effect •Degree of ionization or polarity •Gastric-emptying rate; Intestinal motility •Age, Gender •Genetics •Physical activity •Drug interactions How is bioavailability affected by oral administration of drugs? - Orally administered drugs must pass through the intestinal wall and then the portal circulation to the liver; both are common sites of first-pass metabolism, or metabolism that occurs before a drug reaches the systemic circulation. Thus, many drugs may be metabolized before adequate plasma concentrations are reached.
Low bioavailability is most common with oral dosage forms of poorly water-soluble, slowly absorbed drugs Insufficient time for absorption in the GI tract is a common cause of? - low bioavailability. If the drug does not dissolve readily or cannot penetrate the epithelial membrane (eg, if it is highly ionized and polar), time at the absorption site may be insufficient. In such cases, bioavailability tends to be highly variable as well as low. Give an example of a direct drug interaction and an indirect - Such interactions may be direct, as in chelation of tetracycline by polyvalent metal ions in antacids or the absorption of digoxin by cholestyramine resin; or indirect, as with the increased rate of acetaminophen absorption due to the increased gastric emptying rate produced by metoclopramide. Most of the reported drug-drug interactions have resulted in a reduction in the rate and/or extent of drug absorption, the most frequent causes being complexing of a drug with other substances, reduced GI motility and alterations in drug ionization
