Drug Absorption and Distribution L3 Flashcards
Pharmacokinetics definition
The study of the change in drug and metabolite
concentrations in tissues and body fluids
Why understand pharmacokinetics ?
To know how to get drugs to their site of action at above the therapeutic concentration, but below a toxic concentration, for the needed period of time i.e. inside a “therapeutic window”
Therapeutic ratio and drug safety
Therapeutic ratio (or index) =maximum non toxic dose / minimum therapeutic dose
One way of calculating this more formally it to measure:
therapeutic ration = TD50 / ED50
TD50= the toxic dose of a drug for 50% of the population ED50= the minimum effective dose for 50% of the population
Such measurements can be made in either animals or humans.The safest drugs have a high therapeutic ratio.
ADME
Absorption: movement of a drug from the point of administration to the plasma
Distribution: from plasma to tissues and organs
Metabolism of drugs by enzymes in body
Excretion of drug/metabolite by body
ADME is very important for
- Drug development
- Understanding toxicity
- Establishing route of administration
- Establishing drug dose
- Understanding possible drug interactions
Absorption - bioavailability
“Fraction of unchanged drug that reaches systemic circulation”
Decrease by:
- Poorer absorption
- First pass metabolism (first pass)
NB: IV drug delivery has 100% bioavailability
What is absorption dependent on ?
1) route of administration.
2) chemical nature of compound: lipophilicity (the higher the better), charge (uncharged is faster), size (smaller is faster).
3) Formulation: a key area in pharmacy research.
4) Blood flow rate to the site of delivery
Formulation examples
Generally speaking:
- Liquids absorb faster than capsules/tablets because of the greater area for exchange.
- Gelatin-coating tablets (eg Non Steroidal Anti Inflammatory Drugs such as aspirin, ibuprofen) slows absorption and decreases local peak concentrations.
- Capsules containing granules with differently soluble coatings allows (controlled release).
- Intramuscular injection of an oily depot (decanoate) of lipophilic drugs (eg. haloperidol) allows very slow release (eg. anti-psychotic drugs in non-compliant patients).
3 routes of administration
Intravenous(IV)
Sublingual (sl; under the tongue / buccal)
Orally (po) / Rectally (pr)
- fastest to slowest
Types of administration , speed and risks
- Intravenous(IV): fast but invasive with infection risk
- Intramuscular(IM)/Subcutaneous(sc): fairly fast, but invasive/painful and can cause local reactions; can be slowly 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
- 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
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
Cell Membranes
- Very impermeable to charged molecules
- Even K+ ions going through channels cross 10,000,000 times slower than they diffuse in water
- Lipophilic molecules cross membrane (ideally less than 400mol. wt.)
- Pinocytosis for particulate material
pH and its effect on drug movement
across membranes
Weak Bases
Protonated form is charged, so (more alkaline) then there will be more uncharged (unprotonated) form present, and drug will cross membranes.
-NH3+ <---> -NH2 + H+
Weak Acids
Protonated form is uncharged, so under more acid conditions then there will be more uncharged form present, and drug will cross membranes.
-COOH <—> - COO- + H+
pH and its effect on drug movement
across membranes
- Differences in pH can determine where drugs will accumulate
- Drugs tend to accumulate wherever they are ionized, as it is difficult for them to leave such compartments.
First Pass Metabolism
For an enteral (oral or rectal) route of administration, drug crossing the gut wall will have* to traverse 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).
Enterohepatic circulation
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
Distribution
“How drugs equilibrate within the body after entering the systemic circulation”.
Common fates:
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)
The destination of drugs also depends on the blood flow to particular organs: (Brain, Heart, Liver) > Muscle (at rest) > Adipose tissue
Volume of Distribution
“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”
Vd = D / Cp
where D=amount of drug (mg) and Cp=concentration of drug in the plasma (mg/L)
NB: Often given in units of Vd/body mass (i.e. L/kg), in which case you need to multiply by body mass prior to calculating
Why is this useful? By knowing Vd, you can calculate the dose (D) required to hit a target concentration (Cp).
Drug binding to circulating proteins
Observation: many drugs bind to circulating proteins, particularly albumin.
Key Ideas:
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.
Examples of drugs bound by albumin
Both warfarin and salicylates (including aspirin) bind to circulating plasma proteins. When more than one of these drugs is present, there can be competition for binding, increasing the free drug concentration.
Clinical trials suggest that this effect is small and not detectable, mainly because of the large number of non-specific binding sites available.
