Pharmokinetics Flashcards
The journey of a drug through the body stages
ADME administration absorption distribution metabolism excretion
Routes of administration
dermal intramuscular subcutaneous intraperitoneal intravenous inhalation ingestion
routes of administration can be local or systemic- explain what this means
systemic = the entire organism is getting exposed to the drug
local = restricted to one area of the organism
routes of administration can also be divided into enteral or parenteral- what does this mean?
enteral = via the GI tract
(usually easier)
Parenteral = everything but the GI tract
Explain how absorption works
Drug goes to the GI tract and gets absorbed and taken to the liver
Travels to the liver via the hepatic portal system and then enters the systemic circulation
(Inhalation is also a good route )
Systemic exposure very quickly = intravenous
What are the two ways in which drug molecules move around the body
bulk flow transfer = in the bloodstream it will move in bulk to the tissues
diffusional transfer = molecule by molecule over short distances
what is the main problem with drugs being absorbed?
drugs have to transverse both lipid and aqueous environments
give examples of compartments
Compartments = Aqueous e.g. Blood, lymph, extra-cellular fluid, intra-cellular fluid
give examples of barriers
Barriers = Lipid i.e. cell membranes (epithelium/endothelium)
how can drugs cross these barriers?
NB: non-polar substances can freely dissolve in non-polar solvents ie can penetrate lipid membranes easily
- simple diffusion
- diffusion across aqueous pores (if they are polar - least relevant mode of transport as its v small)
- carrier mediated transport
- pinocytosis
Most drugs are either
weak acids or weak bases/
therefore, drugs exist in ionised (polar) and non-ionised (non-polar) forms- the ratio depends on the pH
the ratio of ionised and non-ionised depends on?
the pH of the environment and the pKa of the molecules
which one is more lipid soluble- ionised or unionised?
the unionised form
The unionized forms of aspirin and morphine are going to be more lipid soluble than the ionized (charged) forms of the drugs. Charged molecules are more polar and thus less lipid soluble and will find it difficult to cross membranes.
pH will be a huge determinant of absorption of drugs across lipid membranes. Weak acids will be more unionized in acidic environments and weak bases will be more unionized in alkaline environments.
what would happen to aspirin and morphin at physiological pH 7.4?
aspirin would be more likely to donate protons and morphine to accept protons
is aspirin acidic or basic?
what is the pKa of aspirin
acidic
3.4
what happens when aspirin enters the stomach
stomach has a pH of 1, which is less than the pKa of aspirin so it is persuaded to be non-ionised
Henderson-hasselbach equation
If we rearrange the equation for the weak base above - then pKa-pH is the power of the exponent that 10 is raised to in order to get [BH+]/[B] i.e. 10^[pKa-pH] = [BH+]/[B]. 10^x is also often referred to as the antilog of x. In this case x = pKa-pH.
**pKa of drug does not change pH of different body compartments
Morphine has a pKa of 8.0
pH in the stomach is 3
Does B or BH+
predominate?
Ionised (BH+) dominates
100000
Aspirin has a pKa of 3.5
The pH in stomach is 3
Does AH or A-
predominate ?
Unionised dominates (AH) 3.16
Describe the passage of aspirin through the stomach and the small intestine
So aspirin exists mainly in the non - ionised form in the stomach meaning that it can readily diffuse across the lipid bilayer (a s it is non - polar) • Eventually the aspirin will make it into the small intestine where the pH is much more basic • As the pH of the small intestine is greater than the pKa of aspirin, the aspirin becomes ionised • Once it is ionised it is much more difficult t o get through the membrane • So in the small intestine a much greater proportion of aspirin is ionised than non - ionised so there is much slower absorption in the small intestine than in the stomach • The ratio of ionised: non - ionised is all dictated by the pH of the environment relative to the pKa of the drug • Once it goes through the liver and into the systemic circulation, the aspirin is in an aqueous environment so you find a proportion of aspirin in an ionised form - it is effectively TRAPPED -THIS IS CALLED ION TRAPPING
Exercise 5: Why might treatment with intravenous sodium bicarbonate increase aspirin excretion?
Acids in higher pH = more ionised, less lipid soluble and therefore excreted.
Factors influencing drug distribution
Regional blood flow
Extracellular binding (Plasma-protein binding)
Capillary permeability (tissue alterations – renal, hepatic, brain/CNS, placental)
Localisation in tissues
How does regional blood flow work?
Tissues that are well perfused are likely to be exposed to higher concentrations of the drug.
Some tissues may increase in perfusion when their activity increases eg skeletal muscle
Highly metabolically active tissues tend to have a greater blood flow and denser network of capillaries.
How does extracellular binding (plasma protein binding work?
If a plasma protein is bound to the drug then it is no longer available for absorption
50-80% tend to be bound to plasma proteins
Albumin can bind both the unionised and ionised type of drugs
There are small gaps between endothelial cells that are water filled (aqueous) and so
ionised aspirin
can pass through these gaps
How does Capillary permeability work?
Lipid soluble drugs have good access to all tissues (even the brain) and will be well distributed across body tissues.
Water soluble drugs have poor access to tissues and are dependant on saturable carrier proteins for access to tissues. As a result, they tend to be less well distributed across body tissues.
•Distribution also depends quite heavily on capillary architecture oFenestrated -more permeable to drugs oContinuous -found in normal vessels, has water -filled gap junctions oDiscontinuous -large gaps between endothelial cell
How does localisation in tissues work?
** fat isn’t usually highly perfused, so it is a very lipophilic environment, so drugs that are lipophilic tend to localise in fatty tissue. Fat soluble drugs highly partition into fatty tissues eg brain and testes
Blood flow to the body fat is very low – approximately 2% of the cardiac output. As a result, at any given moment in time, only small amounts of the non-ionised drug is being delivered to the body fat.
The lipid solubility of the drug. We mentioned morphine above. Morphine can access the brain, which suggests it is fairly lipid soluble. However, its oil/water partition coefficient (i.e how well it dissolves in fat versus how well it dissolves in water) is 1. If 98% of the drug is being distributed to body water (i.e. other tissues) and only 2% of it to body fat, then very little will distribute to body fat. However, some drugs have high oil/water partition coefficients. For example some general anaesthetics can have an oil/water partition coefficient of 5000. As a result, the 2% that reaches the body fat will accumulate in this tissue very effectively. The drug that resides in the body fat will then slowly leak back into the bloodstream (due to the poor blood flow to this tissue and the preference of the drug for the body fat versus the aqueous blood)
What are the two major routes of excretion?
Liver- some drugs are concentrated in the bile
Kidney- ultimately responsible for the elimination of most drugs
How are drugs eliminated from the kidney?
- glomerular filtration (size dependent) -glomerulus
- active secretion (dependent on available transporters) -proximal tubule
- passive reabsorption- dependent on urine pH and extent of drug metabolism (for lipid soluble drugs)
How does liver work in drug excretion?
Biliary excretion allows the concentration of large molecular weight molecules that are very lipophilic
there are also active transport systems that secrete drugs into bile. The active transport systems are geared for the transport of bile acids
and glucuronides
into the bile-drugs hitch a ride on this because they
are non-polar and have a large molecular weight
what is enterohepatic cycling?
drug/metabolite excreted into gut (via bile) then reabsorbed, taken to liver
and excreted again
what are the problems with enterohepatic cycling?
Biliary excretion can cause problems because of enterohepatic cycling
oThe drug or metabolite gets excreted into the gut but then it can get
reabsorbed and returned to the liver via the enterohepatic circulation
oThis leads to
drug persistence
What are the other routes of drug excretion?
lungs, skin, gastrointestinal secretions, saliva, sweat
Define bioavailability
Bioavailability (linked to absorption)
Proportion of the administered drug that is available within the body to exert its pharmacological effect
Define apparent volume of distribution
Apparent volume of distribution (linked to distribution)
The volume in which a drug appears to be distributed
- an indicator of the pattern of distribution
Define biological half-life
Biological half-life (linked to metabolism/excretion)
Time taken for the concentration of drug (in blood/plasma) to fall to half its original value
Define clearance
Clearance (linked to excretion)
Blood (plasma) clearance is the volume of blood (plasma) cleared of a drug (i.e. from which the drug is completely removed) in a unit time
(Related to volume of distribution and the rate at which the drug is eliminated. If clearance involves several processes, then total clearance is the sum of these processes.)
