s2-L18-Absorption and Distribution of drugs-A&D Flashcards
(25 cards)
Define PHARMACOKINETICS (PK)
the study of the change in drug and metabolite concentrations in tissues and body fluids.
OR
what the body does to a drug
OR
how drug travel into and out of the body
why understand pharmacokinetics? conc of drug and time graph
to know how to get drugs to their site of action at above the minimum therapeutic concentration, but below a toxic concentration for the needed period of time(therapeutic window).
Give the equation for therapeutic ratio
maximum non-toxic dose / minimum therapeutic dose
The safest drugs have a low or high therapeutic ratio?
HIGH
What is the acronym for pharmacokinetics and write it in full
ADME
A - Absorption - movement of a drug from the point of administration to the plasma
D - distribution - from plasma to tissues and organs.
M - metabolism of drugs by enzymes in body
E - Excretion of drug/metabolite by body
What does ADME allows us to understand ? 5 things?
-Drug development
-Understanding toxicity
-Establishing route of administration(injection, gummies, orally)
-Establishing drug dose
-Understanding possible drug interactions
Absorption definition and what is absorption decreased by ?
-fraction of unchanged drug that reaches systemic circulation
-Decreased by - poorer absorption, 1st pass metabolism
IV drug delivery has 100% bioavailability
Absorption depends on 4 things?
1) route of administration.
2) chemical nature of compound: lipophilicity (the higher the better), charge (uncharged is faster), size (smaller is faster).
3) Formulation: ie:-lipid soluble formulation >faster absorption so don’t need for the drug to disperse.
4) Blood flow rate to the site of delivery
1). Name different routes of administration
- Intravenous(IV) - inject to the vein directly (fastest)
👇 - sublingual(under the tongue/buccal)
(medium)
👇 - orally(po) / rectally (pr) - long pathway
(slowest)
-orally means by mouth- then has to go through stomach, s.i , l.i , liver, drug absorbed.
rectally means into the rectum then absorbed through rectal wall and into the liver. for people with difficulties swallowing, vomiting, nausea.
Describe the 3 routes of administrations in more detail.
-Intravenous(IV): fast but invasive with infection risk
-Intramuscular(IM)/Subcutaneous(sc)[underneath the skin]: fairly fast, but invasive/painful and can cause local reactions in stomach by aspirin; can be slowly[bc crossing an epithelium barrier] absorbed in the case of a lipophilic drug injected in lipid.
-Sublingual (sl): fast, but only a very small amount can be absorbed, so requires very potent drugs. -under the tongue, a spray into the mouth> no large s.a for the drug to dissolve.
-Orally (po) / Rectally (pr): slow, with first pass metabolism, but non-invasive; mostly absorbed through small intestine.
-Transcutaneous: only suitable for some drugs; lipophilic carrier needed to cross the skin.> drug within/inside a lipid carrier.
Examples of formulation
- Liquids absorb faster than capsules/tablets because of the greater area for exchange.(cough syrups)
- Gelatin-coating tablets (eg Non Steroidal Anti
Inflammatory Drugs such as aspirin[causes local damage in stomach], ibuprofen) slows
absorption and decreases local peak concentrations. - Capsules containing granules with differently soluble coatings allows (controlled release).
- Intramuscular[inject drugs to muscles] injection of an oily depot (decanoate-do not disperse, stay near muscle cells) of
lipophilic drugs (eg. haloperidol) allows very slow release (eg. anti-psychotic drugs in non-compliant patients).
-muscles has a reasonable high blood supply.
Things to consider for absorption from the gastrointestinal tract (enteral absorption)
- Consider interactions with food
- Consider the rate of transit in the gut
- For oral delivery, consider the pH sensitivity, given the need to pass through the stomach
- Consider First Pass Metabolism(👇ses the bioavailability of the drug)>
Describe the graphs for the Effect of rate of absorption via the gut on plasma concentration- Rapid Absorption
-quick to target concentration
-higher peak concentration
-briefer duration of action
Describe the graph for Effect of rate of absorption via the gut on plasma concentration - sow absorption
-Slow to target concentration
-lower peak concentration
-marginally longer duration of action
Name few epithelial barriers in controlling drug entry into cells and to charged molecules?
- straight through - lipid soluble
-paracellular route - water soluble
-transporter channels for ions
-pinocytosis - particulate material
VERY IMPERMEABLE to charged molecules!!!!
How does the changes in pH levels has an effect on drug movement across membranes ?
-differences in pH can determine where drugs will accumulate(collect/increase in number).
-drugs tend to accumulate wherever they are IONIZED, as it is difficult for them to leave such compartments.
Define first pass metabolism
-For an enteral (oral or rectal) route of
administration, drug crossing the gut wall will
have* to traverse(move through) the liver. The metabolism of drugs before they first reach the systemic circulation is referred to as “first pass metabolism”.
-First pass metabolism greatly limits the use of many potential drugs, because of metabolism in the gut or liver.
*Except for those lipophilic drugs absorbed via
lacteals (lymphatics).
extra:
When a drug is taken orally, it is absorbed in the gastrointestinal tract and transported via the hepatic portal vein to the liver, where it undergoes first-pass metabolism. This process can significantly reduce the concentration of the active drug before it reaches systemic circulation, meaning less of the drug is available to exert its intended effect.
Define Enterohepatic circulation and examples of drugs and implications of this route.
Some drugs entering the gut are absorbed, enter the portal circulation, pass from liver (with or without conjugation) to bile then back to the intestinal tract.
Implications: extended half life, sensitive to bowel conjugation
Examples: commonly used drugs (morphine, warfarin, indomethacin, cardiac
glycosides), antimicrobial agents (clindamycin, rifampicin, erythromycin,
metronidazole, ampicillin, ceftriaxone and doxycycline), radiocontrast media.
Define Distribution from ADME
-How drugs equilibrate/distribute within the body after entering the systemic circulation.
Some 😊and 😔 of distribution in ADME
- No distribution (for large drugs or those binding to plasma proteins; eg heparin)
- Distribute through the extracellular space (modified by natural barriers such as the blood brain barrier and placenta)
- Distribute throughout total body water
- Accumulate in cells (eg. specific transporters; bretylium)
- Distribute to fat (for lipophilic drugs; inhaled anaesthetics)
Define volume of distribution and examples
The volume of fluid required to contain the total amount of drug in the body at the same concentration as that present in the plasma.
ie:-
- Heparin: A large molecule, confined to the plasma.
- Insulin: Strongly bound to plasma proteins
- Gentamicin: A strongly polar molecule (extracellular space)
- Ethanol: High water and fat solubility
- Tetrahydrocannabinol (THC):Preferential fat distribution
Why is volume of distribution useful ?
By knowing Vd, you can calculate the dose(D) required to hit a target concentration(Cp)
What does the destination of the drug depends on ?
-depends on the blood flow to particular organs (🧠, ♥, liver) > 💪 (at rest) > adipose tissue
Why are there some drugs binding to circulating proteins? and what happens?
-Many drugs bind to circulating proteins, particularly albumin.
-It is the free concentration of a drug that determines its action.
Binding therefore:-
-decreases the initial free concentration
-slows distribution
-slows clearance
-prolongs duration of action
