Absorption and distribution week 1 Flashcards
pharmacodynamics
pharmacokinetics
pharmacodynamics: effects drugs have on the body
pharmacokinetics: effects the body has on the drug
What is the range of molecular weights for most therapeutic drugs?
Why is size of drugs important?
Why is it not beneficial for drugs to be large in size? How are very large drugs typically administered?
Most therapeutic drugs have molecular weights between 100 and 1000. Size is critical for receptor fit and activation. The upper limit in molecular weight is determined primarily by the requirement that drugs must be able to move within the body (e.g., site of administration to the site of action).
Drugs much larger than MW 1000 do not diffuse readily between compartments of the body. Therefore, very large drugs (usually proteins) must often be administered directly into the compartment where they have their effect. In the case of alteplase, a clot-dissolving enzyme, the drug is administered directly into the vascular compartment by intravenous or intra-arterial infusion.
What are the processes of pharmacokinetics?
Pharmacokinetics: the dynamics of drug Abosorption, Distribution, Metabolism, & Excretion (ADME)
In order to understand and control the therapeutic action of drugs in the human body, one must know how much drug will reach the site(s) of drug action and when this will occur. The absorption, distribution, metabolism (biotransformation), and elimination of drugs are the processes of pharmacokinetics. Understanding and employing pharmacokinetic principles can increase the probability of therapeutic success and reduce the occurrence of adverse drug effects in the body.
Explain the mechanisms of drug permeation into cells.
What is the dominant mode of permeatio for most drugs? (diffusion or active transport?)
Drugs may diffuse passively through aqueous channels in the intercellular junctions (A) (e.g., tight junctions), through lipid cell membranes (B). Drugs with the appropriate characteristics may be transported by carriers into or out of cells. Very impermeant drugs may also bind to cell surface receptors (dark binding sites) (C), be engulfed by the cell membrane (endocytosis), and then released inside the cell or expelled via the membrane-limited vesicles out of the cell into the extracellular space (exocytosis, D).
P-glycoprotein-function and location
An important efflux transporter is the P-glycoprotein encoded by the multidrug resistance-1 (MDR1) gene. P-glycoprotein localized in the enterocyte, limits the oral absorption of transported drugs because it exports compounds back into the lumen of the GI tract subsequent to their absorption by passive diffusion.
____ ____ is the most important limiting factor for drug permeation.
Explain why.
Lipid diffusion is the most important limiting factor for drug permeation because of the large number of lipid barriers that separate the compartments of the body. Because these lipid barriers separate aqueous compartments, the lipid:aqueous partition coefficient of a drug determines how readily the molecule moves between aqueous and lipid media.
What determines transmembrane distribution of a weak acid or base?
What equation is used to determime this?
Many drugs are weak acids or bases that are present in solution as both the non-ionized and ionized species. The non-ionized molecules usually are more lipid-soluble and can diffuse readily across the cell membrane. In contrast, the ionized forms usually are less able to penetrate the lipid membrane because of their low lipid solubility, and passage will depend on the leakiness of the membrane related to the membrane’s electrical resistance. Therefore, the transmembrane distribution of a weak electrolyte is influenced by its pKa and the pH gradient across the membrane. The pKa is the pH at which half the drug (weak acid or base electrolyte) is in its ionized form.
Henderson-Hasselbach equation is used to determine this. See pg 12 of course notes
Define absorption?
What determines absorption?
Absorption is the process of uptake of a compound from the site of administration into the systemic circulation. The absorptive phase is governed by the time and amount (that is, the rate) of absorption.
What is the drug loss on administration of drugs given intravasculalry? bioavailability?
• Intravascular
– No absorption phase
– No drug loss on administration
– Bioavailability =100%
Name examples of extravascular routes of adminstration.
What is the role of absorption in extravascular routes of administration?
Relatively, what is the importance of bioavailability in extravascular routes of adminstration?
Extravascular
– e.g., Oral, Intramuscular, Subcutaneous, Intradermal, Transdermal, Inhalation, Rectal
– Requires absorption
– May have drug loss
– Bioavailability very important
Cmax
tmax
How does rate of absorption effect the above parameters?
The rate of absorption determines the required time for the administered drug to reach an effective plasma concentration and may thus affect the onset of the drug effect. This rate influences both the peak plasma concentration (Cmax) and the time it takes to reach this peak (tmax).
Variation of the rate of absorption can add to the global pharmacokinetic variability, particularly in patients with diseases affecting the absorption site (e.g. affections of the gastro-intestinal tract).
Name mechanical and physiochemical determinants of absorption.
Some Determinants of Absorption
A. Mechanical:
- Disintegration- the time for the preparation (e.g. pill) to be reduced to fragments. (Liberation)
- Dissolution- the time for the drug to disperse into a solution, i.e. to dissolve.
- These processes are subject to variance from manufacturer to manufacturer and may result in Bio-inequivalence due to different disintegrations, dissolutions, and affect rate and extent of absorption.
B. Physiochemical:
- Molecular size- the larger the molecule the less likely to cross membranes.
- The degree of ionization of the compound. Charged molecules do not readily cross
membranes.
Most drugs are organic compounds and can be categorized as:
A. Non-electrolytes, e.g. glucose. These drugs do not ionize, and pH changes do not affect th absorption and distribution of this kind of drug.
B. Weak acids or bases. Those drugs that donate protons are weak acids (aspirin, barbiturates). Those drugs that accept protons are weak bases (norepinephrine, epinephrine). Strong acids or bases are not used systemically as medicines. HCl is the only physiologic strong acid used clinically and it is found in the stomach. The most important point to remember is that ionized drugs do not pass through membranes. Therefore the degree of ionization is important in determining the ability and extent of drug movement across membranes.
- Lipid partition coefficient – does the compound have some solubility in water and lipid to get to membranes and pass through them.
zero-order drug absorption
first-order drug absorption
The mechanism of drug absorption is said to be zero-order when the rate is independent of the amount of drug remaining in the gut, eg, when it is determined by the rate of gastric emptying or by a controlled-release drug formulation. In contrast, when the dose is dissolved in gastrointestinal fluids, the rate of absorption is usually proportional to the gastrointestinal concentration and is said to be first-order.
sustained release
What is the purpose of giving a sustained release drug?
controlled release
Sustained release is simply a prolongation in the time it takes to absorb a drug from the absorption site, usually the small intestine. The outcome is to prolong therapeutic blood or tissue levels for an extended period of time, usually allowing a greater longer dosing interval (less # of doses per day), which improves adherence (compliance).
Controlled release: Rate controlling drug delivery systems, which are able to specify the release rate and duration in vivo precisely, and can be considered as a form of controlled release that it exercises spatial control of drug release within the body.
attached slide found on college website
What is the first oral absorptive surface?
What is the relative amount of absorption that takes place here and why?
What are benefits to giving medication sublingually?
ORAL ADMINISTRATION: (per os, po)
Approximately 80% of drugs prescribed in the U.S. are for oral administration. This route is used largely for convenience, ease of administration, less toxicity, and lower expense.
The first oral absorptive surface is the buccal (between the inside cheek and gums) mucosa. Due to the rapid transit time, usually very little absorption takes place here. Special drug formulations are sublingual (SL = sublingual) and buccal. Nitroglycerin is an example of a drug which is formulated to dissolve quickly in the mouth and is rapidly absorbed in ≈1-2 min. The nitroglycerin tablet is placed under the tongue to relieve angina (chest pain) associated with coronary spasm. This route will also eliminate the hepatic first pass effect which can be associated with the oral route of drug administration.
Define the following routes of adminstration.
State the absorption patterns, circumstances they are used in, and limitations/precautions for IV, SQ, IM, and PO routes.
intrathecal
intradermal
intramuscular (IM)
subcutaneous (SQ)
topical
transdermal
inhalation
eye and ear drops
intranasal
intrasynovial
parenteral
- intrathecal - injection into CSF to obtain effective concentration in the CNS.
- intradermal - injection into the dermal layer, ex. local anesthesia.
- intramuscular - injection into muscles of the arm or buttocks; used for irritating drugs, drugs not absorbed by the oral route or when a depot of drug is required. The rate of absorption can be altered by formulation (type of suspension, size of crystal) and application of heat, cold, or exercise. This route of administration was quite popular before the onset of the AIDS/HIV epidemic, and as a caution against occupational needle sticks, a switch to IV administration occurred. Risks of IM include local infections, accidental intravascular administration, nerve damage, and pain experienced by the patient.
- subcutaneous - injection under the skin; absorption is slower than for IV or IM and less predictable. Insulin and heparin are administered SQ.
- topical - application to skin; usually for local effect. There will be a dermal lecture in Block Six.
- transdermal - transdermal patch used with drugs like fentanyl, nitroglycerin, scopolamine, and hormones are applied topically for sustained absorption into systemic circulation. This is an area of rapid product development.
- inhalation - gaseous anesthetics are often given for systemic effect. This route is rapid due to the large surface area of the lung. Gaseous anesthetics, bronchodilators, emergency administration of resuscitative medications are some classes of drugs administered by this route. Local and systemic effects occur with this route. (bronchodilators and anti-inflammatories in asthma.)
- eye & ear drops - applied topically for local effects. May lead to systemic toxicity.
Intranasal Local and Systemic effects – local and systemic; systemic changes in bioavailability and Tmax
Intrasynovial Injection into a joint space
PARENTERAL – OUTSIDE THE GUT – INCLUDES INJECTIONS, VASCULAR ACCESS, ANYTHING OTHER THAN ORAL, TOPICAL, RECTAL, VAGINAL, URETHRAL
What are the benefits of IV infusions? In what circumstances are IV infusions used?
IV infusion is a useful means to control both the rate of administration and obtain a desired response (even over an extended period of time). The IV route is used when drugs would be inactivated by gastric enzymes or acid (npo patient). It is also used for drugs which are poorly absorbed, or can cause irritation in tissues if injected IM. This method is fast and can be used to maintain a desired blood level over a long period of time. IV drip is a special case where the drug is administered dropwise (i.e. so many drops, or a specific dose, per unit time). More commonly, pumps are routinely used to deliver IV ‘drips’ or infusions.
How is bioavailability (F) calculated?
Bioavailability (F) is determined by calculating the fraction of an extravascular dose absorbed compared to the IV administered dose (same dose and drug). This is done by taking blood samples at timed intervals and comparing the area under the curve (AUC) for oral and for IV administration. The AUC is proportional to the amount of drug in the systemic circulation.
F= AUCpo/AUCIV
Define bioequivalence.
Define bioinequivalence.
Bioequivalence compares two different manufacturers’ products of the same drug (e.g. brand name “Brand A” vs generic prep. “Brand B”) or two different drugs (e.g. drug X vs drug Y).
Bioequivalence has two requirements:
a) same bioavailability
b) same rate of absorption
Note: bio-inequivalence may occur even if two drugs have equal bioavailability. Brand A and Brand B have equal bioavailability according to their AUC’s. However, Brand B is absorbed more slowly.
